Heteroaryl compounds and methods of use thereof

ABSTRACT

Provided herein are thiophene compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.

I. FIELD

Provided herein are thiophene compounds useful for treating variousneurological disorders, including but not limited to, psychosis andschizophrenia, compositions comprising the compounds, and methods of usethereof.

II. BACKGROUND

Central nervous system disorders affect a wide range of the populationwith differing severity. Generally, the major feature of this class ofdisorders includes the significant impairment of cognition or memorythat represents a marked deterioration from a previous level offunctioning.

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked bycharacteristics such as, psychotic symptoms, phasic progression anddevelopment, and/or deterioration in social behavior and professionalcapability. Characteristic psychotic symptoms are disorders of thoughtcontent (e.g., multiple, fragmentary, incoherent, implausible or simplydelusional contents, or ideas of persecution) and of mentality (e.g.,loss of association, flight of imagination, incoherence up toincomprehensibility), as well as disorders of perceptibility (e.g.,hallucinations), emotions (e.g., superficial or inadequate emotions),self-perceptions, intentions, impulses, and/or inter-humanrelationships, and psychomotoric disorders (e.g., catatonia). Othersymptoms are also associated with this disorder. See, e.g., Diagnosticand Statistical Manual of Mental Disorders, 4^(th) Ed., AmericanPsychiatric Association (1997) (DSM-IV™).

Schizophrenia is classified into subgroups. The paranoid type ischaracterized by delusions and hallucinations and absence of thoughtdisorder, disorganized behavior, and affective flattening. Thedisorganized type, which is also named “hebephrenic schizophrenia,” inwhich thought disorder and flat affect are present together. Thecataconic type, in which prominent psychomotor disturbances are evident,and symptoms may include catatonic stupor and waxy flexibility. Theundifferentiated type in which psychotic symptoms are present but thecriteria for paranoid, disorganized, or catatonic types have not beenmet. The symptoms of schizophrenia normally manifest themselves in threebroad categories, i.e., positive, negative and cognitive symptoms.Positive symptoms are those, which represent an “excess” of normalexperiences, such as hallucinations and delusions. Negative symptoms arethose where the patient suffers from a lack of normal experiences, suchas anhedonia and lack of social interaction. The cognitive symptomsrelate to cognitive impairment in schizophrenics, such as lack ofsustained attention and deficits in decision making. The currentantipsychotics may be successful in treating the positive symptoms butfare less well for the negative and cognitive symptoms.

Cognitive impairment includes a decline in cognitive functions orcognitive domains, e.g., working memory, attention and vigilance, verballearning and memory, visual learning and memory, reasoning and problemsolving (e.g., executive function, speed of processing and/or socialcognition). In particular, cognitive impairment may indicate deficits inattention, disorganized thinking, slow thinking, difficulty inunderstanding, poor concentration, impairment of problem solving, poormemory, difficulties in expressing thoughts, and/or difficulties inintegrating thoughts, feelings and behavior, or difficulties inextinction of irrelevant thoughts.

Agitation is a well-recognized behavioral disorder with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and/or uncooperativeness. Agitation is common in the elderly andoften associated with dementia such as those caused by Alzheimer'sdisease, Parkinson's disease, and Huntington's disease, and by diseasesthat affect blood vessels, such as stroke or multi-infarct dementia,which is caused by multiple strokes in the brain. An estimated fivepercent of people aged 65 and older and up to 20 percent of those aged80 and older are affected by dementia; of these sufferers, nearly halfexhibit behavioral disturbances, such as agitation, wandering, andviolent outbursts. Agitated behaviors can also be manifested incognitively intact elderly people and by those with psychiatricdisorders other than dementia.

Dementia is characterized by several cognitive impairments includingsignificant memory deficit and can stand alone, or be an underlyingcharacteristic feature of a variety of diseases, including but notlimited to, Alzheimer's disease, Parkinson's disease, Huntington'sdisease, and multiple sclerosis.

Therefore, there is a great need for effective treatments of variousneurological disorders, including but not limited to, psychosis andschizophrenia.

III. SUMMARY

Provided herein are compounds of formula (I), or pharmaceuticallyacceptable salts or stereoisomers thereof:

wherein R^(1a), R^(1b), R², and R³ are defined herein elsewhere. Thecompounds are useful for treating various disorders, such asneurological disorders including, but not limited to, psychosis andschizophrenia.

Also provided herein are compositions and dosage forms, comprising acompound provided herein, and one or more pharmaceutically acceptableexcipients. Compositions and dosage forms provided herein may furthercomprise one or more additional active ingredients.

Also provided herein are methods for the treatment, prevention, and/ormanagement of various neurological disorders, including those of thecentral nervous system (CNS) using the compounds and compositionsprovided herein. In one embodiment, provided herein is a method oftreating or managing one or more symptoms of a neurological disorderprovided herein. Such neurological disorders include, but are notlimited to, schizophrenia, schizophrenia spectrum disorder, acuteschizophrenia, chronic schizophrenia, NOS schizophrenia, schizoidpersonality disorder, schizotypal personality disorder, delusionaldisorder, psychosis, psychotic disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, drug-induced psychosis (e.g., cocaine, alcohol, amphetamine),psychoaffective disorder, aggression, delirium, Parkinson's psychosis,excitative psychosis, Tourette's syndrome, organic or NOS psychosis,seizure, agitation, post-traumatic stress disorder, behavior disorder,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,dyskinesias, Huntington's disease, dementia, mood disorder, anxiety,affective disorders (e.g., depression, e.g., major depressive disorderand dysthymia; bipolar disorder, e.g., bipolar depressive disorder;manic disorder; seasonal affective disorder; and attention deficitdisorder (ADD) and attention deficit hyperactivity disorder (ADHD)),obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g.,neuropathic pain, sensitization accompanying neuropathic pain, andinflammatory pain), fibromyalgia, migraine, cognitive impairment,cognitive impairment associated with schizophrenia (CIAS), movementdisorder, restless leg syndrome (RLS), multiple sclerosis, sleepdisorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jetlag, drowsy side effect of medications, insomnia, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, autism, Huntington's chorea, and premenstrual dysphoria.

In one embodiment, provided herein is a method of treating, preventing,and/or managing psychosis or schizophrenia. In one embodiment, providedherein is a method of treating or managing one or more symptoms ofpsychosis or schizophrenia. In one embodiment, provided herein is amethod of treating, preventing, and/or managing psychosis orschizophrenia in a subject, such as a mammal, such as, e.g., human,rodent (such as, e.g., mice and rats), cat, dog, non-human primate,among others. In one embodiment, the method comprises contacting acompound provided herein with one or more receptors of the centralnervous system. In one embodiment, the method comprises contacting acell with a compound provided herein. In an exemplary embodiment, thecell is a brain cell, such as, e.g., a neuronal cell or a glial cell.

IV. DETAILED DESCRIPTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as those commonly understood by one of ordinaryskill in the art. In certain embodiments, abbreviations are as definedin J. Org. Chem. 2007, 72, 23A. All publications and patents referred toherein are incorporated by reference herein in their entireties.

A. Definitions

As used in the specification and the accompanying claims, the indefinitearticles “a” and “an” and the definite article “the” include plural aswell as singular referents, unless the context clearly dictatesotherwise.

As used herein, and unless otherwise indicated, the term “alkyl” refersto a linear or branched saturated monovalent hydrocarbon radical,wherein the alkyl may optionally be substituted with one or moresubstituents. In certain embodiments, the alkyl is a linear saturatedmonovalent hydrocarbon radical that has 1 to 20 (C₁₋₂₀), 1 to 15(C₁₋₁₅), 1 to 12 (C₁₋₁₂), 1 to 10 (C₁₋₁₀), or 1 to 6 (C₁₋₆) carbonatoms, or branched saturated monovalent hydrocarbon radical of 3 to 20(C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6(C₃₋₆) carbon atoms. As used herein, linear C₁₋₆ and branched C₃₋₆ alkylgroups are also referred as “lower alkyl.” Examples of alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl (including allisomeric forms, e.g., n-propyl and isopropyl), butyl (including allisomeric forms, e.g, n-butyl, isobutyl, and t-butyl), pentyl (includingall isomeric forms), and hexyl (including all isomeric forms). Forexample, C₁₋₆ alkyl refers to a linear saturated monovalent hydrocarbonradical of 1 to 6 carbon atoms or a branched saturated monovalenthydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, thealkyl is optionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkenyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbondouble bonds. The alkenyl may be optionally substituted with one or moresubstituents. The term “alkenyl” also encompasses radicals having “cis”and “trans” configurations, or alternatively, “E” and “Z”configurations, as appreciated by those of ordinary skill in the art.For example, C₂₋₆ alkenyl refers to a linear unsaturated monovalenthydrocarbon radical of 2 to 6 carbon atoms or a branched unsaturatedmonovalent hydrocarbon radical of 3 to 6 carbon atoms. In certainembodiments, the alkenyl is a linear monovalent hydrocarbon radical of 2to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12 (C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2to 6 (C₂₋₆) carbon atoms, or a branched monovalent hydrocarbon radicalof 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to 12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀),or 3 to 6 (C₃₋₆) carbon atoms. Examples of alkenyl groups include, butare not limited to, ethenyl, propen-1-yl, propen-2-yl, allyl, butenyl,and 4-methylbutenyl. In certain embodiments, the alkenyl is optionallysubstituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkynyl”refers to a linear or branched monovalent hydrocarbon radical, whichcontains one or more, in one embodiment, one to five, carbon-carbontriple bonds. The alkynyl may be optionally substituted with one or moresubstituents. In certain embodiments, the alkynyl is a linear monovalenthydrocarbon radical of 2 to 20 (C₂₋₂₀), 2 to 15 (C₂₋₁₅), 2 to 12(C₂₋₁₂), 2 to 10 (C₂₋₁₀), or 2 to 6 (C₂₋₆) carbon atoms, or a branchedmonovalent hydrocarbon radical of 3 to 20 (C₃₋₂₀), 3 to 15 (C₃₋₁₅), 3 to12 (C₃₋₁₂), 3 to 10 (C₃₋₁₀), or 3 to 6 (C₃₋₆) carbon atoms. Examples ofalkynyl groups include, but are not limited to, ethynyl (—C≡CH) andpropargyl (—CH₂C≡CH). For example, C₂₋₆ alkynyl refers to a linearunsaturated monovalent hydrocarbon radical of 2 to 6 carbon atoms or abranched unsaturated monovalent hydrocarbon radical of 3 to 6 carbonatoms. In certain embodiments, the alkynyl is optionally substituted asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term “cycloalkyl”refers to a cyclic fully or partially saturated bridged and/ornon-bridged hydrocarbon radical or ring system, which may be optionallysubstituted with one or more substituents. In certain embodiments, thecycloalkyl has from 3 to 20 (C₃₋₂₀), from 3 to 15 (C₃₋₁₅), from 3 to 12(C₃₋₁₂), from 3 to 10 (C₃₋₁₀), or from 3 to 7 (C₃₋₇) carbon atoms.Examples of cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,decalinyl, and adamantyl. In certain embodiments, the cycloalkyl isoptionally substituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “heteroalkyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three,heteroatoms selected from the group consisting of O, N, Si, and S, andwherein the nitrogen and sulfur atoms are optionally oxidized and thenitrogen heteroatom can optionally be quaternized. In one embodiment,the heteroatom(s) O, N and S can be placed at any interior position ofthe heteroalkyl group. In one embodiment, the heteroatom Si can beplaced at any position of the heteroalkyl group (e.g., interior orterminal position), including the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to, —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, and —CH═CH—N(CH₃)—CH₃. Up to two heteroatomscan be consecutive, such as, for example, —CH₂—NH—O—CH₃ and—CH₂—O—Si(CH₃)₃. In certain embodiments, the heteroalkyl is optionallysubstituted as described herein elsewhere.

As used herein, and unless otherwise specified, the term “alkoxyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three, Oatoms. Examples of alkoxyl include, but are not limited to, —O—CH₃,—O—CF₃, —O—CH₂—CH₃, —O—CH₂—CH₂—CH₃, —O—CH—(CH₃)₂, and —O—CH₂—CH₂—O—CH₃.In one embodiment, the alkoxyl is optionally substituted as describedherein elsewhere.

As used herein, and unless otherwise specified, the term “aminoalkyl”refers to a stable straight or branched chain, or cyclic hydrocarbonradical, or combinations thereof, consisting of the stated number ofcarbon atoms and from one or more, in one embodiment, one to three, Natoms. Examples of aminoalkyl include, but are not limited to, —NH—CH₃,—N(CH₃)₂, —NH—CH₂—CH₃, —N(CH₃)—CH₂—CH₃, —NH—CH—(CH₃)₂, —CH₂—CH₂—NH—CH₃,and —CH₂—CH₂—N(CH₃)₂. In one embodiment, the aminoalkyl is optionallysubstituted as described herein elsewhere. In some embodiments, theaminoalkyl is optionally substituted with one or more halo.

As used herein, and unless otherwise specified, the term “aryl” refersto an optionally substituted monocyclic or multicyclic radical or ringsystem that contains at least one aromatic hydrocarbon ring. In certainembodiments, the aryl has from 6 to 20, from 6 to 15, or from 6 to 10ring atoms. Examples of aryl groups include, but are not limited to,phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl,biphenyl, and terphenyl. In certain embodiments, aryl also refers tobicyclic, tricyclic, or tetracyclic carbon rings, where one of the ringsis aromatic and the other(s) of the rings may be saturated, partiallyunsaturated, or aromatic, for example, dihydronaphthyl, indenyl,indanyl, or tetrahydronaphthyl(tetralinyl). In certain embodiments, arylmay be a bicyclic, tricyclic, or tetracyclic ring system, where at leastone of the rings is aromatic and one or more of the ring(s) is/aresaturated or partially unsaturated containing one or more heteroatomsindependently selected from O, S, and N. In certain embodiments, thearyl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term “arylalkyl” or“aralkyl” refers to a monovalent alkyl group substituted with aryl.Example of aralkyl includes, but is not limited to, benzyl. In certainembodiments, both alkyl and aryl may be optionally substituted with oneor more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term“cycloalkylalkyl” refers to a monovalent alkyl group substituted withcycloalkyl. In certain embodiments, both the alkyl and cycloalkyl may beoptionally substituted with one or more substituents as described hereinelsewhere.

As used herein, and unless otherwise specified, the term “heteroaryl”refers to an optionally substituted monocyclic or multicyclic radical orring system which contains at least one aromatic ring having one or moreheteroatoms independently selected from O, S, and N. In one embodiment,each ring of a heteroaryl group can contain one or two O atoms, one ortwo S atoms, and/or one to four N atoms, provided that the total numberof heteroatoms in each ring is four or less and each ring contains atleast one carbon atom. In certain embodiments, the heteroaryl has from 5to 20, from 5 to 15, or from 5 to 10 ring atoms. In certain embodiments,heteroaryl also refers to bicyclic, tricyclic, or tetracyclic rings,where one of the rings is aromatic having one or more heteroatomsindependently selected from O, S, and N, and the other(s) of the ringsmay be saturated, partially unsaturated, or aromatic and may becarbocyclic or contain one or more heteroatoms independently selectedfrom O, S, and N. Examples of monocyclic heteroaryl groups include, butare not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl,triazinyl, and triazolyl. Examples of bicyclic heteroaryl groupsinclude, but are not limited to, benzofuranyl, benzimidazolyl,benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl,benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl,imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl,isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl,isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl,pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl,quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl.Examples of tricyclic heteroaryl groups include, but are not limited to,acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl,phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, theheteroaryl is optionally substituted with one or more substituents asdescribed herein elsewhere.

As used herein, and unless otherwise specified, the term“heterocycloalkyl” or “heterocyclyl” refers to an optionally substitutedmonocyclic or multicyclic radical or ring system which contains at leastone non-aromatic ring having one or more heteroatoms independentlyselected from O, S, and N, and the remaining ring atoms are carbonatoms. In certain embodiments, the heterocyclyl or heterocycloalkylgroup has from 3 to 20, from 3 to 15, from 3 to 10, from 3 to 8, from 4to 7, or from 5 to 6 ring atoms. In certain embodiments, theheterocyclyl or heterocycloalkyl is a monocyclic, bicyclic, tricyclic,or tetracyclic ring system, which may include a fused or bridged ringsystem, and in which the nitrogen or sulfur atoms may be optionallyoxidized, the nitrogen atoms may be optionally quaternized, the ringcarbon atoms may be optionally substituted with oxo, and some rings maybe partially or fully saturated, or aromatic. The heterocycloalkyl orheterocyclyl may be attached to the main structure at a heteroatom or acarbon atom which results in the creation of a stable compound. Examplesinclude, but are not limited to, azepinyl, benzodioxanyl, benzodioxolyl,benzofuranonyl, benzopyranonyl, benzopyranyl, benzotetrahydrofuranyl,benzotetrahydrothienyl, benzothiopyranyl, benzoxazinyl, β-carbolinyl,chromanyl, chromonyl, cinnolinyl, coumarinyl, decahydroisoquinolinyl,dihydrobenzisothiazinyl, dihydrobenzisoxazinyl, dihydrofuryl,dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl,dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl,1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl,isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl, isochromanyl,isocoumarinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl,morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl,oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl,pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl,tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl,and 1,3,5-trithianyl. In certain embodiments, when the heterocyclyl orheterocycloalkyl ring contains one or more 0, the heterocyclyl orheterocycloalkyl may also be referred to as “cycloalkoxyl.” In certainembodiments, the heterocyclyl or heterocycloalkyl is optionallysubstituted with one or more substituents as described herein elsewhere.

As used herein, and unless otherwise specified, the term “halogen”,“halide” or “halo” refers to fluorine, chlorine, bromine, and iodine.

As used herein, and unless otherwise specified, the term “hydrogen”encompasses proton (¹H), deuterium (²H), tritium (³H), and/or mixturesthereof. In a compound described herein, one or more positions occupiedby hydrogen may be enriched with deuterium and/or tritium. Suchisotopically enriched analogs may be prepared from suitable isotopicallylabeled starting material obtained from a commercial source or preparedusing known literature procedures.

The term “combination treatment,” as used herein, encompassesadministration of two or more agents to a subject so that both agentsand/or their metabolites are present in the subject at the same time.Combination treatment can include simultaneous administration inseparate compositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

As used herein, and unless otherwise specified, the term “optionallysubstituted” is intended to mean that a group, such as an alkyl,alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, aralkyl,cycloalkylalkyl, heteroaryl, or heterocyclyl, may be substituted withone or more substituents independently selected from, e.g., (a) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, and heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; and (b) halo, cyano (—CN), nitro (—NO₂), —C(O)R^(a), —C(O)OR^(a),—C(O)NR^(b)R^(c), —C(NR^(a))NR^(b)R^(c), —OR^(a), —OC(O) R^(a),—OC(O)OR^(a), —OC(O)NR^(b)R^(c), —OC(═NR^(a))NR^(b)R^(c), —OS(O)R^(a),—OS(O)₂R^(a), —OS(O)NR^(b)R^(c), —OS(O)₂NR^(b)R^(c), —NR^(b)R^(c),—NR^(a)C(O)R^(d), —NR^(a)C(O)OR^(d), —NR^(a)C(O)NR^(b)R^(c),—NR^(a)C(═NRd)NR^(b)R^(c), —NR^(a)S(O)R^(d), —NR^(a)S(O)₂R^(d),—NR^(a)S(O)NR^(b)R^(c), —NR^(a)S(O)₂NR^(b)R^(c), —SR^(a), —S(O)R^(a),—S(O)₂R^(a), —S(O)NR^(b)R^(c), and —S(O)₂NR^(b)R^(c), wherein eachR^(a), R^(b), R^(c), and R^(d) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl, each optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ¹; or (iii) R^(b) and R^(c) together with the N atom to which they areattached form heteroaryl or heterocyclyl, optionally substituted withone or more, in one embodiment, one, two, three, or four, substituentsQ′. As used herein, all groups that can be substituted are “optionallysubstituted,” unless otherwise specified.

In one embodiment, each Q¹ is independently selected from the groupconsisting of (a) cyano, halo, and nitro; and (b) C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅ aralkyl,heteroaryl, and heterocyclyl; and (c) —C(O)R^(e), —C(O)OR^(e),—C(O)NR^(f)R^(g), —C(NR^(e))NR^(f)R^(g), —OR^(e), —OC(O)R^(e),—OC(O)OR^(e), —OC(O)NR^(f)R^(g), —OC(═NR^(e))NR^(f)R^(g), —OS(O)R^(e),—OS(O)₂R^(e), —OS(O)NR^(f)R^(g), —OS(O)₂NR^(f)R^(g), —NR^(f)R^(e),—NR^(e)C(O)R^(h), —NR^(e)C(O)OR^(h), —NR^(e)C(O)NR^(f)R^(g),—NR^(e)C(═NR^(h))NR^(f)R^(g), —NR^(e)S(O)R^(h), —NR^(e)S(O)₂R^(h),—NR^(e)S(O)NR^(f)R^(g), —NR^(e)S(O)₂NR^(f)R^(g), —SR^(e), —S(O)R^(e),—S(O)₂R^(e), —S(O)NR^(f)R^(g), and —S(O)₂NR^(f)R^(g); wherein eachR^(e), R^(f), R^(g), and R^(h) is independently (i) hydrogen; (ii) C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₆₋₁₄ aryl, C₇₋₁₅aralkyl, heteroaryl, or heterocyclyl; or (iii) R^(f) and R^(g) togetherwith the N atom to which they are attached form heteroaryl orheterocyclyl.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic acids, including inorganic acidsand organic acids. Suitable non-toxic acids include inorganic andorganic acids, such as, including but not limited to, acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, gluconic, glutamic, glucorenic,galacturonic, glycidic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, propionic, phosphoric, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonic.

As used herein, and unless otherwise specified, the term “solvate”refers to a compound provided herein or a salt thereof, which furtherincludes a stoichiometric or non-stoichiometric amount of solvent boundby non-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate. In certain embodiments, a compound as disclosedherein may be provided as a solvate. In certain embodiments, a compoundas disclosed herein may be provided as a hydrate.

As used herein, and unless otherwise specified, the term “stereoisomer”encompasses all enantiomerically/diastereomerically/stereomerically pureand enantiomerically/diastereomerically/stereomerically enrichedcompounds provided herein.

As used herein and unless otherwise specified, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80% by weight of one stereoisomer of the compound and lessthan about 20% by weight of other stereoisomers of the compound, greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,greater than about 95% by weight of one stereoisomer of the compound andless than about 5% by weight of the other stereoisomers of the compound,greater than about 97% by weight of one stereoisomer of the compound andless than about 3% by weight of the other stereoisomers of the compound,or greater than about 99% by weight of one stereoisomer of the compoundand less than about 1% by weight of the other stereoisomers of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallyenriched” means a composition that comprises greater than about 55% byweight of one stereoisomer of a compound, greater than about 60% byweight of one stereoisomer of a compound, greater than about 70% byweight, or greater than about 80% by weight of one stereoisomer of acompound.

As used herein, and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center. Similarly, the term “enantiomericallyenriched” means a stereomerically enriched composition of a compoundhaving one chiral center.

In certain embodiments, as used herein, and unless otherwise specified,“optically active” and “enantiomerically active” refer to a collectionof molecules, which has an enantiomeric excess or diastereomeric excessof no less than about 50%, no less than about 70%, no less than about80%, no less than about 90%, no less than about 91%, no less than about92%, no less than about 93%, no less than about 94%, no less than about95%, no less than about 96%, no less than about 97%, no less than about98%, no less than about 99%, no less than about 99.5%, or no less thanabout 99.8%. In certain embodiments, the compound comprises about 95% ormore of the desired enantiomer or diastereomer and about 5% or less ofthe less preferred enantiomer or diastereomer based on the total weightof the racemate in question.

In describing an optically active compound, the prefixes R and S areused to denote the absolute configuration of the molecule about itschiral center(s). The (+) and (−) are used to denote the opticalrotation of the compound, that is, the direction in which a plane ofpolarized light is rotated by the optically active compound. The (−)prefix indicates that the compound is levorotatory, that is, thecompound rotates the plane of polarized light to the left orcounterclockwise. The (+) prefix indicates that the compound isdextrorotatory, that is, the compound rotates the plane of polarizedlight to the right or clockwise. However, the sign of optical rotation,(+) and (−), is not related to the absolute configuration of themolecule, R and S.

As used herein, and unless otherwise specified, the term “about” or“approximately” means an acceptable error for a particular value asdetermined by one of ordinary skill in the art, which depends in part onhow the value is measured or determined. In certain embodiments, theterm “about” or “approximately” means within 1, 2, 3, or 4 standarddeviations. In certain embodiments, the term “about” or “approximately”means within 50%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%,2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range.

As used herein, and unless otherwise specified, the term“pharmaceutically acceptable carrier,” “pharmaceutically acceptableexcipient,” “physiologically acceptable carrier,” or “physiologicallyacceptable excipient” refers to a pharmaceutically-acceptable material,composition, or vehicle, such as a liquid or solid filler, diluent,solvent, or encapsulating material. In one embodiment, each component is“pharmaceutically acceptable” in the sense of being compatible with theother ingredients of a pharmaceutical formulation, and suitable for usein contact with the tissue or organ of humans and animals withoutexcessive toxicity, irritation, allergic response, immunogenicity, orother problems or complications, commensurate with a reasonablebenefit/risk ratio. See, Remington: The Science and Practice ofPharmacy, 21st Edition, Lippincott Williams & Wilkins: Philadelphia,Pa., 2005; Handbook of Pharmaceutical Excipients, 5th Edition, Rowe etal., Eds., The Pharmaceutical Press and the American PharmaceuticalAssociation: 2005; and Handbook of Pharmaceutical Additives, 3rdEdition, Ash and Ash Eds., Gower Publishing Company: 2007;Pharmaceutical Preformulation and Formulation, 2nd Edition, Gibson Ed.,CRC Press LLC: Boca Raton, Fla., 2009.

As used herein, and unless otherwise specified, the terms “activeingredient” and “active substance” refer to a compound, which isadministered, alone or in combination with one or more pharmaceuticallyacceptable excipients, to a subject for treating, preventing, orameliorating one or more symptoms of a condition, disorder, or disease.As used herein, “active ingredient” and “active substance” may be anoptically active isomer of a compound described herein.

As used herein, and unless otherwise specified, the terms “drug” and“therapeutic agent” refer to a compound, or a pharmaceutical compositionthereof, which is administered to a subject for treating, preventing,managing, or ameliorating one or more symptoms of a condition, disorder,or disease.

As used herein, and unless otherwise indicated, the terms “treat,”“treating” and “treatment” refer to the eradication or amelioration of adisease or disorder, or of one or more symptoms associated with thedisease or disorder. In one embodiment, such symptoms are those known toa person of skill in the art to be associated with the disease ordisorder being treated. In certain embodiments, the terms refer tominimizing the spread or worsening of the disease or disorder resultingfrom the administration of one or more prophylactic or therapeuticagents to a subject with such a disease or disorder. In someembodiments, the terms refer to the administration of a compoundprovided herein, with or without other additional active agent, afterthe onset of symptoms of the particular disease.

As used herein, and unless otherwise indicated, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms associated with the disease or disorder. In one embodiment,such symptoms are those known to a person of skill in the art to beassociated with the disease or disorder being prevented. In certainembodiments, the terms refer to the treatment with or administration ofa compound provided herein, with or without other additional activecompound, prior to the onset of symptoms, particularly to patients atrisk of disease or disorders provided herein. The terms encompass theinhibition or reduction of a symptom of the particular disease. Patientswith familial history of a disease in particular are candidates forpreventive regimens in certain embodiments. In addition, patients whohave a history of recurring symptoms are also potential candidates forthe prevention. In this regard, the term “prevention” may beinterchangeably used with the term “prophylactic treatment.”

As used herein, and unless otherwise specified, the terms “manage,”“managing,” and “management” refer to preventing or slowing theprogression, spread or worsening of a disease or disorder, or of one ormore symptoms associated with the disease or disorder. In oneembodiment, such symptoms are those known to a person of skill in theart to be associated with the disease or disorder being managed. Often,the beneficial effects that a subject derives from a prophylactic and/ortherapeutic agent do not result in a cure of the disease or disorder. Inthis regard, the term “managing” encompasses treating a patient who hadsuffered from the particular disease in an attempt to prevent orminimize the recurrence of the disease.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment or management of a disease ordisorder, or to delay or minimize one or more symptoms associated withthe disease or disorder. A therapeutically effective amount of acompound means an amount of therapeutic agent, alone or in combinationwith other therapies, which provides a therapeutic benefit in thetreatment or management of the disease or disorder. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease ordisorder, or enhances the therapeutic efficacy of another therapeuticagent.

As used herein, and unless otherwise specified, a “prophylacticallyeffective amount” of a compound is an amount sufficient to prevent adisease or disorder, or prevent its recurrence. A prophylacticallyeffective amount of a compound means an amount of therapeutic agent,alone or in combination with other agents, which provides a prophylacticbenefit in the prevention of the disease. The term “prophylacticallyeffective amount” can encompass an amount that improves overallprophylaxis or enhances the prophylactic efficacy of anotherprophylactic agent.

As used herein, and unless otherwise specified, the term “subject” isdefined herein to include animals such as mammals, including, but notlimited to, primates (e.g., humans), cows, sheep, goats, horses, dogs,cats, rabbits, rats, mice and the like. In specific embodiments, thesubject is a human.

As used herein, and unless otherwise specified, the term “neurologicaldisorder” refers to any condition of the central or peripheral nervoussystem of a mammal. The term “neurological disorder” includes, but isnot limited to, neurodegenerative diseases (e.g., Alzheimer's disease,Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatricdiseases (e.g., schizophrenia and anxieties, such as general anxietydisorder), and affective disorders (e.g., depression, bipolar disorder,manic conditions, and attention deficit disorder). Exemplaryneurological disorders include, but are not limited to, MLS (cerebellarataxia), Huntington's disease, Down syndrome, multi-infarct dementia,status epilecticus, contusive injuries (e.g., spinal cord injury andhead injury), viral infection induced neurodegeneration, (e.g., AIDS,encephalopathies), epilepsy, benign forgetfulness, closed head injury,sleep disorders, major depressive disorder, dysthymia, seasonalaffective disorder, dementias, movement disorders, psychosis,alcoholism, post-traumatic stress disorder, and the like. “Neurologicaldisorder” also includes any condition associated with the disorder. Forinstance, a method of treating a neurodegenerative disorder includesmethods of treating loss of memory and/or loss of cognition associatedwith a neurodegenerative disorder. An exemplary method would alsoinclude treating or preventing loss of neuronal function characteristicof neurodegenerative disorder. “Neurological disorder” also includes anydisease or condition that is implicated, at least in part, in monoamine(e.g., norepinephrine) signaling pathways (e.g., cardiovasculardisease).

As used herein, and unless otherwise specified, the terms “psychosis,”“schizophrenia,” “obsessive-compulsive disorder,” “substance abuse,”“anxiety,” “eating disorders,” “migraine,” and other CNS or neurologicaldisorders described herein elsewhere are used herein in a mannerconsistent with their accepted meanings in the art. See, e.g.,Diagnostic and Statistical Manual of Mental Disorders, 4^(th) Ed.,American Psychiatric Association (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “seizure”refers to a neurological disorder and may be used interchangeably with“convulsion,” although there are many types of seizure, some of whichhave subtle or mild symptoms instead of convulsions. In one embodiment,the term “seizure” as used herein is intended to encompass “convulsion.”In some embodiments, seizures may be caused by disorganized and suddenelectrical activity in the brain. In some embodiments, convulsions are arapid and uncontrollable shaking during which the muscles contract andrelax repeatedly. Unless otherwise specified, the terms “convulsion” and“seizure” are used herein in accordance with the accepted meanings asfound in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., American Psychiatric Association (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “affectivedisorder” includes depression, attention deficit disorder, attentiondeficit disorder with hyperactivity, bipolar disorder, and manicdisorder, and the like.

As used herein, and unless otherwise specified, the term “depression”includes all forms of depression, including, but not limited to, majordepressive disorder (MDD) or unipolar depressive disorder, dysthymia,seasonal affective disorder (SAD), and bipolar depressive disorder.“Major depressive disorder” is used herein interchangeably with“unipolar depression”, “unipolar depressive disorder”, and “majordepression.” “Depression” may also include any condition commonlyassociated with depression, such as all forms of fatigue (e.g., chronicfatigue syndrome) and cognitive deficits.

Unless otherwise specified, the terms “bipolar disorder” and “manicdisorder” are used herein in accordance with the accepted meanings asfound in the Diagnostic and Statistical Manual of Mental Disorders,4^(th) Ed., American Psychiatric Association (1997) (DSM-IV™).

Unless otherwise specified, the terms “attention deficit disorder”(ADD), and “attention deficit disorder with hyperactivity” (ADDH) or“attention deficit hyperactivity disorder” (ADHD), are used herein inaccordance with the accepted meanings as found in the Diagnostic andStatistical Manual of Mental Disorders, 4^(th) Ed., American PsychiatricAssociation (1997) (DSM-IV™).

As used herein, and unless otherwise specified, the term “pain” refersto an unpleasant sensory and emotional experience. Unless otherwisespecified, the term “pain,” as used herein, refers to all categories ofpain, including pain that is described in terms of stimulus or nerveresponse, e.g., somatic pain (normal nerve response to a noxiousstimulus) and neuropathic pain (abnormal response of a injured oraltered sensory pathway, often without clear noxious input); pain thatis categorized temporally, e.g., chronic pain and acute pain; pain thatis categorized in terms of its severity, e.g., mild, moderate, orsevere; and pain that is a symptom or a result of a disease state orsyndrome, e.g., inflammatory pain, cancer pain, AIDS pain, arthropathy,migraine, trigeminal neuralgia, cardiac ischaemia, and diabeticperipheral neuropathic pain (See, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety). “Pain” is also meant toinclude mixed etiology pain, dual mechanism pain, allodynia, causalgia,central pain, hyperesthesia, hyperpathia, dysesthesia, and hyperalgesia.In one embodiment, the term “pain” includes pain resulting fromdysfunction of the nervous system: organic pain states that shareclinical features of neuropathic pain and possible commonpathophysiology mechanisms, but are not initiated by an identifiablelesion in any part of the nervous system.

Unless otherwise specified, the term “somatic pain,” as used herein,refers to a normal nerve response to a noxious stimulus such as injuryor illness, e.g., trauma, burn, infection, inflammation, or diseaseprocess such as cancer, and includes both cutaneous pain (e.g., skin,muscle or joint derived) and visceral pain (e.g., organ derived).

Unless otherwise specified, the term “neuropathic pain,” as used herein,refers to a heterogeneous group of neurological conditions that resultfrom damage to the nervous system. The term also refers to painresulting from injury to or dysfunctions of peripheral and/or centralsensory pathways, and from dysfunctions of the nervous system, where thepain often occurs or persists without an obvious noxious input. Thisincludes pain related to peripheral neuropathies as well as centralneuropathic pain. Common types of peripheral neuropathic pain includediabetic neuropathy (also called diabetic peripheral neuropathic pain,or DN, DPN, or DPNP), post-herpetic neuralgia (PHN), and trigeminalneuralgia (TGN). Central neuropathic pain, involving damage to the brainor spinal cord, can occur following stroke, spinal cord injury, and as aresult of multiple sclerosis, and is also encompassed by the term. Othertypes of pain that are meant to be included in the definition ofneuropathic pain include, but are not limited to, neuropathic cancerpain, HIV/AIDS induced pain, phantom limb pain, and complex regionalpain syndrome. Unless otherwise specified, the term also encompasses thecommon clinical features of neuropathic pain including, but not limitedto, sensory loss, allodynia (non-noxious stimuli produce pain),hyperalgesia and hyperpathia (delayed perception, summation, and painfulafter sensation). Pain is often a combination of nociceptive andneuropathic types, for example, mechanical spinal pain and radiculopathyor myelopathy.

As used herein, and unless otherwise specified, the term “acute pain”refers to the normal, predicted physiological response to a noxiouschemical, thermal or mechanical stimulus typically associated withinvasive procedures, trauma and disease. It is generally time-limited,and may be viewed as an appropriate response to a stimulus thatthreatens and/or produces tissue injury. The term also refers to painwhich is marked by short duration or sudden onset.

As used herein, and unless otherwise specified, the term “chronic pain”encompasses the pain occurring in a wide range of disorders, forexample, trauma, malignancies and chronic inflammatory diseases such asrheumatoid arthritis. Chronic pain may last more than about six months.In addition, the intensity of chronic pain may be disproportionate tothe intensity of the noxious stimulus or underlying process. The termalso refers to pain associated with a chronic disorder, or pain thatpersists beyond resolution of an underlying disorder or healing of aninjury, and that is often more intense than the underlying process wouldpredict. It may be subject to frequent recurrence.

As used herein, and unless otherwise specified, the term “inflammatorypain” is pain in response to tissue injury and the resultinginflammatory process. Inflammatory pain is adaptive in that it elicitsphysiologic responses that promote healing. However, inflammation mayalso affect neuronal function. Inflammatory mediators, including PGE₂induced by the COX2 enzyme, bradykinins, and other substances, bind toreceptors on pain-transmitting neurons and alter their function,increasing their excitability and thus increasing pain sensation. Muchchronic pain has an inflammatory component. The term also refers to painwhich is produced as a symptom or a result of inflammation or an immunesystem disorder.

As used herein, and unless otherwise specified, the term “visceral pain”refers to pain which is located in an internal organ.

As used herein, and unless otherwise specified, the term “mixed etiologypain” refers to pain that contains both inflammatory and neuropathiccomponents.

As used herein, and unless otherwise specified, the term “dual mechanismpain” refers to pain that is amplified and maintained by both peripheraland central sensitization.

As used herein, and unless otherwise specified, the term “causalgia”refers to a syndrome of sustained burning, allodynia, and hyperpathiaafter a traumatic nerve lesion, often combined with vasomotor andsudomotor dysfunction and later trophic changes. As used herein, andunless otherwise specified, the term “central pain” refers to paininitiated by a primary lesion or dysfunction in the central nervoussystem.

As used herein, and unless otherwise specified, the term “hyperesthesia”refers to increased sensitivity to stimulation, excluding the specialsenses.

As used herein, and unless otherwise specified, the term “hyperpathia”refers to a painful syndrome characterized by an abnormally painfulreaction to a stimulus, especially a repetitive stimulus, as well as anincreased threshold. It may occur with allodynia, hyperesthesia,hyperalgesia, or dysesthesia.

As used herein, and unless otherwise specified, the term “dysesthesia”refers to an unpleasant abnormal sensation, whether spontaneous orevoked. In certain embodiments, dysesthesia include hyperalgesia andallodynia.

As used herein, and unless otherwise specified, the term “hyperalgesia”refers to an increased response to a stimulus that is normally painful.It reflects increased pain on suprathreshold stimulation.

As used herein, and unless otherwise specified, the term “allodynia”refers to pain due to a stimulus that does not normally provoke pain.

As used herein, and unless otherwise specified, the term “diabeticperipheral neuropathic pain” (DPNP), also called diabetic neuropathy, DNor diabetic peripheral neuropathy), refers to chronic pain caused byneuropathy associated with diabetes mellitus. The classic presentationof DPNP is pain or tingling in the feet that can be described not onlyas “burning” or “shooting” but also as severe aching pain. Lesscommonly, patients may describe the pain as itching, tearing, or like atoothache. The pain may be accompanied by allodynia and hyperalgesia andan absence of symptoms, such as numbness.

As used herein, and unless otherwise specified, the term “post-herpeticneuralgia”, also called “postherpetic neuralgia” (PHN), refers to apainful condition affecting nerve fibers and skin. Without being limitedby a particular theory, it is a complication of shingles, a secondoutbreak of the varicella zoster virus (VZV), which initially causeschickenpox.

As used herein, and unless otherwise specified, the term “neuropathiccancer pain” refers to peripheral neuropathic pain as a result ofcancer, and can be caused directly by infiltration or compression of anerve by a tumor, or indirectly by cancer treatments such as radiationtherapy and chemotherapy (chemotherapy-induced neuropathy).

As used herein, and unless otherwise specified, the term “HIV/AIDSperipheral neuropathy” or “HIV/AIDS related neuropathy” refers toperipheral neuropathy caused by HIV/AIDS, such as acute or chronicinflammatory demyelinating neuropathy (AIDP and CIDP, respectively), aswell as peripheral neuropathy resulting as a side effect of drugs usedto treat HIV/AIDS.

As used herein, and unless otherwise specified, the term “phantom limbpain” refers to pain appearing to come from where an amputated limb usedto be. Phantom limb pain can also occur in limbs following paralysis(e.g., following spinal cord injury). “Phantom limb pain” is usuallychronic in nature.

As used herein, and unless otherwise specified, the term “trigeminalneuralgia” (TN) refers to a disorder of the fifth cranial (trigeminal)nerve that causes episodes of intense, stabbing, electric-shock-likepain in the areas of the face where the branches of the nerve aredistributed (lips, eyes, nose, scalp, forehead, upper jaw, and lowerjaw). It is also known as the “suicide disease”.

As used herein, and unless otherwise specified, the term “complexregional pain syndrome” (CRPS), formerly known as “reflex sympatheticdystrophy” (RSD), refers to a chronic pain condition whose key symptomis continuous, intense pain out of proportion to the severity of theinjury, which gets worse rather than better over time. The termencompasses type 1 CRPS, which includes conditions caused by tissueinjury other than peripheral nerve, and type 2 CRPS, in which thesyndrome is provoked by major nerve injury, and is sometimes calledcausalgia.

As used herein, and unless otherwise specified, the term “fibromyalgia”refers to a chronic condition characterized by diffuse or specificmuscle, joint, or bone pain, along with fatigue and a range of othersymptoms. Previously, fibromyalgia was known by other names such asfibrositis, chronic muscle pain syndrome, psychogenic rheumatism andtension myalgias.

B. Compounds

In one embodiment, provided herein is a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from S and O;

one of R^(1a) and R^(1b) is a heterocyclic or heteroaryl ring; and theother of R^(1a) and R^(1b) is selected from hydrogen, halo, cyano,alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, and heteroaryl; or

R^(1a) is a heterocyclic or heteroaryl ring; and taken together, R^(1b)and R² and the atoms to which they are attached form a cycloalkyl, aryl,heterocyclic or heteroaryl ring; and

R² and R³ are each independently selected from hydrogen, halo, cyano,alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl, and heteroaryl; or, taken together, R² and R³ andthe atoms to which they are attached form a cycloalkyl, aryl,heterocyclic or heteroaryl ring.

In one embodiment, provided herein is a compound of formula (I), asdefined herein elsewhere, or a pharmaceutically acceptable salt thereof,wherein:

X is selected from S and O;

one of R^(1a) and R^(1b) is a heterocyclic or heteroaryl ring; and theother of R^(1a) and R^(1b) is selected from hydrogen, halo, alkyl, andaryl; or

R^(1a) is a heterocyclic or heteroaryl ring; and taken together, R^(1b)and R² and the atoms to which they are attached form a cycloalkyl oraryl ring; and

R² and R³ are each independently selected from hydrogen, halo, alkyl,and aryl; or, taken together, R² and R³ and the atoms to which they areattached form a cycloalkyl or aryl ring.

In one embodiment, X is S or O. In one embodiment, X is S. In oneembodiment, X is O.

In one embodiment, R^(1a) is a heterocyclic or heteroaryl ring; andR^(1b) is selected from hydrogen, halo, cyano, alkyl, alkoxyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, andheteroaryl. In one such embodiment, R^(1b) is selected from hydrogen,halogen, alkyl, and aryl. In one such embodiment, R^(1b) is selectedfrom hydrogen, F, Cl, Br, (C₁-C₄)alkyl, and phenyl.

In one embodiment, R^(1a) is a heterocyclic ring and R^(1b) is hydrogen.In one embodiment, R^(1a) is a heterocyclic ring and R^(1b) is halo. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is cyano. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is alkyl. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is alkoxyl. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is alkenyl. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is alkynyl. Inone embodiment, R^(1a) is a heterocyclic ring and R^(1b) is cycloalkyl.In one embodiment, R^(1a) is a heterocyclic ring and R^(1b) iscycloalkylalkyl. In one embodiment, R^(1a) is a heterocyclic ring andR^(1b) is aryl. In one embodiment, R^(1a) is a heterocyclic ring andR^(1b) is aralkyl. In one embodiment, R^(1a) is a heterocyclic ring andR^(1b) is heterocyclyl. In one embodiment, R^(1a) is a heterocyclic ringand R^(1b) is heteroaryl.

In one embodiment, R^(1a) is a heteroaryl ring and R^(1b) is hydrogen.In one embodiment, R^(1a) is a heteroaryl ring and R^(1b) is halo. Inone embodiment, R^(1a) is a heteroaryl ring and R^(1b) is cyano. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is alkyl. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is alkoxyl. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is alkenyl. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is alkynyl. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is cycloalkyl. In oneembodiment, R^(1a) is a heteroaryl ring and R^(1b) is cycloalkylalkyl.In one embodiment, R^(1a) is a heteroaryl ring and R^(1b) is aryl. Inone embodiment, R^(1a) is a heteroaryl ring and R^(1b) is aralkyl. Inone embodiment, R^(1a) is a heteroaryl ring and R^(1b) is heterocyclyl.In one embodiment, R^(1a) is a heteroaryl ring and R^(1b) is heteroaryl.

In one embodiment, R^(1b) is a heterocyclic or heteroaryl ring; andR^(1a) is selected from hydrogen, halo, cyano, alkyl, alkoxyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, andheteroaryl. In one such embodiment, R^(1a) is selected from hydrogen,halogen, alkyl, and aryl. In one such embodiment, R^(1a) is selectedfrom hydrogen, F, Cl, Br, (C₁-C₄)alkyl, and phenyl.

In one embodiment, R^(1b) is a heterocyclic ring and R^(1a) is hydrogen.In one embodiment, R^(1b) is a heterocyclic ring and R^(1a) is halo. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is cyano. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is alkyl. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is alkoxyl. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is alkenyl. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is alkynyl. Inone embodiment, R^(1b) is a heterocyclic ring and R^(1a) is cycloalkyl.In one embodiment, R^(1b) is a heterocyclic ring and R^(1a) iscycloalkylalkyl. In one embodiment, R^(1b) is a heterocyclic ring andR^(1a) is aryl. In one embodiment, R^(1b) is a heterocyclic ring andR^(1a) is aralkyl. In one embodiment, R^(1b) is a heterocyclic ring andR^(1a) is heterocyclyl. In one embodiment, R^(1b) is a heterocyclic ringand R^(1a) is heteroaryl.

In one embodiment, R^(1b) is a heteroaryl ring and R^(1a) is hydrogen.In one embodiment, R^(1b) is a heteroaryl ring and R^(1a) is halo. Inone embodiment, R^(1b) is a heteroaryl ring and R^(1a) is cyano. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is alkyl. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is alkoxyl. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is alkenyl. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is alkynyl. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is cycloalkyl. In oneembodiment, R^(1b) is a heteroaryl ring and R^(1a) is cycloalkylalkyl.In one embodiment, R^(1b) is a heteroaryl ring and R^(1a) is aryl. Inone embodiment, R^(1b) is a heteroaryl ring and R^(1a) is aralkyl. Inone embodiment, R^(1b) is a heteroaryl ring and R^(1a) is heterocyclyl.In one embodiment, R^(1b) is a heteroaryl ring and R^(1a) is heteroaryl.

In one embodiment, R^(1a) is a heterocyclic or heteroaryl ring; andtaken together, R^(1b) and R² and the atoms to which they are attachedform a cycloalkyl, aryl, heterocyclic or heteroaryl ring.

In one embodiment, R^(1a) is a heterocyclic ring; and taken together,R^(1b) and R² and the atoms to which they are attached form acycloalkyl, aryl, heterocyclic or heteroaryl ring. In one embodiment,R^(1a) is a heterocyclic ring; and taken together, R^(1b) and R² and theatoms to which they are attached form a cycloalkyl ring. In oneembodiment, R^(1a) is a heterocyclic ring; and taken together, R^(1b)and R² and the atoms to which they are attached form an aryl ring. Inone embodiment, R^(1a) is a heterocyclic ring; and taken together,R^(1b) and R² and the atoms to which they are attached form aheterocyclic ring. In one embodiment, R^(1a) is a heterocyclic ring; andtaken together, R^(1b) and R² and the atoms to which they are attachedform a heteroaryl ring.

In one embodiment, R^(1a) is a heteroaryl ring; and taken together,R^(1b) and R² and the atoms to which they are attached form acycloalkyl, aryl, heterocyclic or heteroaryl ring. In one embodiment,R^(1a) is a heteroaryl ring; and taken together, R^(1b) and R² and theatoms to which they are attached form a cycloalkyl ring. In oneembodiment, R^(1a) is a heteroaryl ring; and taken together, R^(1b) andR² and the atoms to which they are attached an aryl ring. In oneembodiment, R^(1a) is a heteroaryl ring; and taken together, R^(1b) andR² and the atoms to which they are attached form an a heterocyclic ring.In one embodiment, R^(1a) is a heteroaryl ring; and taken together,R^(1b) and R² and the atoms to which they are attached form a heteroarylring.

In one embodiment, the ring formed by R^(1b) and R² is a cycloalkyl oraryl ring. In one embodiment, the ring formed by R^(1b) and R² is acyclopentyl, cyclohexyl or phenyl ring. In one embodiment, the ringformed by R^(1b) and R² is cyclopentyl, cyclohexyl or phenyl, each ofwhich is optionally substituted with halo, alkyl, or alkoxyl. In oneembodiment, the ring formed by R^(1b) and R² is cyclopentyl, cyclohexyl,or phenyl, each of which is optionally substituted with F, Cl, Br,(C₁-C₄)alkyl or (C₁-C₄)alkoxyl. In one embodiment, the ring formed byR^(1b) and R² is an optionally substituted cyclohexyl. In oneembodiment, the ring formed by R^(1b) and R² is unsubstitutedcyclohexyl. In one embodiment, the ring formed by R^(1b) and R² is anoptionally substituted aryl ring (e.g., phenyl). In one embodiment, thering formed by R^(1b) and R² is an unsubstituted phenyl ring. In oneembodiment, the ring formed by R^(1b) and R² is a monosubstituted phenylring (e.g., 3-chlorophenyl or 4-chlorophenyl).

In one embodiment, R² and R³ are each independently selected fromhydrogen, halo, cyano, alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl.

In one embodiment, R² is hydrogen. In one embodiment, R² is halo (e.g.,chloro). In one embodiment, R² is cyano. In one embodiment, R² is alkyl(e.g., methyl or ethyl). In one embodiment, R² is alkoxyl. In oneembodiment, R² is alkenyl. In one embodiment, R² is alkynyl. In oneembodiment, R² is cycloalkyl. In one embodiment, R² is cycloalkylalkyl.In one embodiment, R² is aryl (e.g., phenyl). In one embodiment, R² isaralkyl. In one embodiment, R² is heterocyclyl. In one embodiment, R² isheteroaryl. In one embodiment, R² is selected from hydrogen, halogen,alkyl, and aryl. In one embodiment, R² is selected from hydrogen, F, Cl,Br, (C₁-C₄)alkyl, and phenyl.

In one embodiment, R³ is hydrogen. In one embodiment, R³ is halo (e.g.,fluoro or bromo). In one embodiment, R³ is cyano. In one embodiment, R³is alkyl (e.g., methyl or ethyl). In one embodiment, R³ is alkoxyl. Inone embodiment, R³ is alkenyl. In one embodiment, R³ is alkynyl. In oneembodiment, R³ is cycloalkyl. In one embodiment, R³ is cycloalkylalkyl.In one embodiment, R³ is aryl (e.g., phenyl or 4-fluorophenyl). In oneembodiment, R³ is aralkyl. In one embodiment, R³ is heterocyclyl. In oneembodiment, R³ is heteroaryl. In one embodiment, R³ is selected fromhydrogen, halogen, alkyl, and aryl. In one embodiment, R³ is selectedfrom hydrogen, F, Cl, Br, (C₁-C₄)alkyl, and phenyl.

In one embodiment; taken together, R² and R³ and the atoms to which theyare attached form a cycloalkyl, aryl, heterocyclic or heteroaryl ring.In one embodiment, R² and R³ and the atoms to which they are attachedform a cycloalkyl ring. In one embodiment, taken together, R² and R³ andthe atoms to which they are attached form an aryl ring. In oneembodiment, taken together, R² and R³ and the atoms to which they areattached form a heterocyclic ring. In one embodiment, taken together, R²and R³ and the atoms to which they are attached form a heteroaryl ring.

In one embodiment, the ring formed by R² and R³ is a cycloalkyl or arylring. In one embodiment, the ring formed by R² and R³ is a cyclopentyl,cyclohexyl or phenyl ring. In one embodiment, the ring formed by R² andR³ is a cyclopentyl, cyclohexyl or phenyl ring, each of which isoptionally substituted with halo, alkyl or alkoxyl. In one embodiment,the ring formed by R² and R³ is a cyclopentyl, cyclohexyl or phenylring, each of which is optionally substituted with F, Cl, Br,(C₁-C₄)alkyl or (C₁-C₄)alkoxyl.

In one embodiment, the ring formed by R² and R³ is an optionallysubstituted cyclopenyl. In one embodiment, the ring formed by R² and R³is unsubstituted cyclopentyl. In one embodiment, the ring formed by R²and R³ is an optionally substituted cyclohexyl. In one embodiment, thering formed by R² and R³ is unsubstituted cyclohexyl. In one embodiment,the ring formed by R² and R³ is an optionally substituted aryl (e.g.,phenyl). In one embodiment, the ring formed by R² and R³ isunsubstituted phenyl. In one embodiment, the ring formed by R² and R³ ismonosubstituted phenyl (e.g., 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-methylphenyl or4-methoxyphenyl). In one embodiment, the ring formed by R² and R³ isdisubstituted phenyl (e.g., 3,4-dichlorophenyl).

In one embodiment, one of R^(1a) and R^(1b) is selected from adihydropyrimidine, dihydroquinazoline, and pyrimidine group.

In one embodiment, R^(1a) is selected from a dihydropyrimidineandpyrimidine group. In one embodiment, R^(1a) is a dihydropyrimidinegroup. In one embodiment, R^(1a) is a pyrimidine group.

In one embodiment, R^(1b) is selected from a dihydropyrimidine, andpyrimidine group. In one embodiment, R^(1b) is a dihydropyrimidinegroup. In one embodiment, R^(1b) is a pyrimidine group.

In one embodiment, one of R^(1a) and R^(1b) is selected from a1,6-dihydropyrimidine, a 1,4-dihydropyrimidineand a pyrimidine.

In one embodiment, R^(1a) is a 1,6-dihydropyrimidine, a1,4-dihydropyrimidine, or a pyrimidine. In one embodiment, R^(1a) is a1,6-dihydropyrimidine. In one embodiment, R^(1a) is a1,4-dihydropyrimidine. In one embodiment, R^(1a) is a pyrimidine.

In one embodiment, R^(1b) is a 1,6-dihydropyrimidine, a1,4-dihydropyrimidine, and a pyrimidine. In one embodiment, R^(1b) is a1,6-dihydropyrimidine. In one embodiment, R^(1b) is a1,4-dihydropyrimidine. In one embodiment, R^(1b) is a pyrimidine.

In one embodiment, one of R^(1a) and R^(1b) is a heterocyclic orheteroaryl ring; and the other of R^(1a) and R^(1b) is selected fromhydrogen, halo, cyano, alkyl, alkoxyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and heteroaryl; providedthat the other of R^(1a) and R^(1b) is not a 1,6-dihydropyrimidine, a1,4-dihydropyrimidine, or a pyrimidine ring.

In one embodiment, one of R^(1a) and R^(1b) is a 1,6-dihydropyrimidine,a 1,4-dihydropyrimidine, or a pyrimidine ring; and the other of R^(1a)and R^(1b) is selected from hydrogen, halo, cyano, alkyl, alkoxyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl,heterocyclyl, and heteroaryl; provided that the other of R^(1a) andR^(1b) is not a 1,6-dihydropyrimidine, a 1,4-dihydropyrimidine, or apyrimidine ring.

In one embodiment, either R^(1a) and R^(1b) is selected from adihydropyrimidine and pyrimidine group; and the other of R^(1a) andR^(1b) is selected from hydrogen, halo, cyano, alkyl, alkoxyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, aryl, and aralkyl; or R^(1a) isselected from a dihydropyrimidine and a pyrimidine; and taken together,R^(1b) and R² and the atoms to which they are attached form anoptionally substituted 4 to 7 membered cycloalkyl, aryl, heterocyclic orheteroaryl ring, preferably a cycloalkyl or aryl ring.

In one embodiment, R^(1a) is hydrogen. In one embodiment, R^(1a) isalkyl (e.g., methyl or ethyl). In one embodiment, R^(1a) is halo (e.g.,fluoro or chloro). In one embodiment, R^(1a) is aryl (e.g., phenyl,2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl or 4-fluorophenyl). Inone embodiment, R^(1a) is heterocyclyl.

In one embodiment, R^(1a) is selected from:

wherein R⁵ is selected from hydrogen, alkyl, and cycloalkyl;

-   R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,    halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl, alkynyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, zheterocyclyl, and    heteroaryl; or R⁷ and R⁸ together with the atoms to which they are    attached form an aryl, heteroaryl, cycloalkyl, or heterocyclyl ring.

In one embodiment, R⁵ is selected from hydrogen and (C₁-C₄)alkyl.

In one embodiment, R⁶, R⁷, R⁸, R⁹ are each independently selected fromhydrogen, halogen, alkyl, alkoxyl, amino, alkylamino, cycloalkyl andaryl.

In one embodiment, R^(1a) is represented by the following structure:

In one embodiment, R⁷ and R⁸ are each independently selected fromhydrogen, halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl,alkynyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is hydrogen or alkyl; and R⁶, R⁷, and R⁸ are eachindependently selected from hydrogen, halo, amino, alkylamino, alkyl,alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is alkyl (e.g.,methyl or ethyl).

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁶ is alkyl (e.g.,methyl, ethyl or isopropyl). In one embodiment, R⁶ is alkoxy (e.g.,methoxy). In one embodiment, R⁶ is cycloalkyl (e.g., cyclopropyl). Inone embodiment, R⁶ is halo (e.g., chloro). In one embodiment, R⁶ isamino. In one embodiment, R⁶ is alkylamino (e.g., dimethylamino ormethylamino). In one embodiment, R⁶ is aryl (e.g., phenyl,4-fluorophenyl or 3-fluorophenyl). In one embodiment, R⁷ is hydrogen. Inone embodiment, R⁷ is alkyl (e.g., methyl). In one embodiment, R⁷ iscycloalkyl (e.g., cyclopropyl). In one embodiment, R⁸ is hydrogen. Inone embodiment, R⁸ is halo (e.g., chloro or fluoro). In one embodiment,R⁸ is alkyl (e.g., methyl, ethyl or isopropyl). In one embodiment, R⁸ iscycloalkyl (e.g., cyclopropyl). In one embodiment, R⁸ is alkoxy (e.g.,methoxy). In one embodiment, R⁸ is aryl (e.g., phenyl, 4-fluorophenyl or3-chlorophenyl).

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R⁷ and R⁸ together with the atoms to which they areattached form an aryl, cycloalkyl, heterocyclyl, or heteroaryl ring.

In one embodiment, R^(1a) is selected from:

-   Y is S or O;-   R¹⁰ is hydrogen or alkyl; and-   R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each    independently selected from hydrogen, halo, amino, alkylamino,    alkyl, alkoxyl, cycloalkyl, and aryl.

In one embodiment, R¹⁰ is hydrogen or (C₁-C₄)alkyl.

In one embodiment, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ areeach independently selected from hydrogen, halo, alkyl, alkoxyl, amino,alkylamino, aryl, or cycloalkyl.

In one embodiment, R^(1a) is

In one embodiment, R¹⁰ is hydrogen.

In one embodiment, R¹¹ is hydrogen.

In one embodiment, R¹², R¹³, R¹⁴ and R¹⁵ are each hydrogen.

In one embodiment, R^(1a) is

In one embodiment, R¹⁰ is hydrogen.

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is alkyl(e.g., methyl).

In one embodiment, R¹², R¹³, R¹⁴ and R¹⁵ are each hydrogen.

In one embodiment, R^(1a) is

In one embodiment, Y is S.

In one embodiment, R¹⁰, R¹¹, R¹⁷ and R¹⁸ are each hydrogen.

In one embodiment, R^(1a) is

In one embodiment, R¹⁰, R¹¹, R¹⁷ and R¹⁹ are each hydrogen.

In one embodiment, R^(1a) is

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is(C₁-C₄)alkyl (e.g., methyl).

In one embodiment, R¹⁰, R¹⁷, R¹⁸ and R¹⁹ are each hydrogen.

In one embodiment, R¹⁰ is hydrogen or alkyl; and R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected fromhydrogen, halo (e.g., chloro, fluoro or bromo), and alkyl (e.g.,methyl).

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R^(1a) is represented by the following structure:

In one embodiment, R⁵ is hydrogen or alkyl; and R⁶, R⁸ and R⁹ are eachindependently selected from hydrogen, halo, amino, alkylamino, alkyl,alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is alkyl (e.g., ethyl, 2-methoxyethyl or2-hydroxyethyl).

In one embodiment, R⁶, R⁸ and R⁹ are hydrogen.

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R^(1a) is represented by the following structure:

In one embodiment, R⁶, R⁸ and R⁹ are each independently selected fromhydrogen, halo, amino, alkylamino, alkyl, alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁶ is aryl (e.g.,phenyl).

In one embodiment, R⁸ and R⁹ are hydrogen.

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R^(1a) is selected from the following:

In one embodiment, R^(1b) is hydrogen. In one embodiment, R^(1b) isalkyl (e.g., methyl or ethyl. In one embodiment, R^(1b) is halo (e.g.,fluoro, chloro or bromo). In one embodiment, R^(1b) is aryl (e.g.,phenyl or 4-fluorophenyl).

In one embodiment, R^(1b) is selected from:

wherein R⁵ is selected from hydrogen, alkyl, and cycloalkyl;

-   R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,    halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl, alkynyl,    cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, and    heteroaryl; or R⁷ and R⁸ together with the atoms to which they are    attached form an aryl, heteroaryl, cycloalkyl, or heterocyclyl ring.

In one embodiment, R^(1b) is represented by the following structure:

In one embodiment, R⁷ and R⁸ are each independently selected fromhydrogen, halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl,alkynyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is hydrogen or alkyl; and R⁶, R⁷, R⁸ and R⁹ areeach independently selected from hydrogen, halo, amino, alkylamino,alkyl, alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is (C₁-C₄)alkyl(e.g., methyl or ethyl).

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁶ is (C₁-C₄)alkyl(e.g., methyl, ethyl or isopropyl). In one embodiment, R⁶ is(C₁-C₄)alkoxyl (e.g., methoxy or ethoxy). In one embodiment, R⁶ isamino. In one embodiment, R⁶ is alkylamino (e.g., methylamino,ethylamino or dimethylamino). In one embodiment, R⁶ is cycloalkyl (e.g.,cyclopropyl). In one embodiment, R⁶ is halo (e.g., chloro). In oneembodiment, R⁶ is aryl (e.g., phenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl or 4-fluorophenyl).

In one embodiment, R⁷ is hydrogen. In one embodiment, R⁷ is (C₁-C₄)alkyl(e.g., methyl or ethyl).

In one embodiment, R⁸ is hydrogen. In one embodiment, R⁸ is (C₁-C₄)alkyl(e.g., methyl, ethyl or isopropyl). In one embodiment, R⁸ is halo (e.g.,fluoro, chloro or bromo). In one embodiment, R⁸ is (C₁-C₄)alkoxy (e.g.,methoxy). In one embodiment, R⁸ is cycloalkyl (e.g., cyclopropyl). Inone embodiment, R⁸ is aryl (e.g., phenyl, 2-fluorophenyl or3-fluorophenyl).

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R⁷ and R⁸ together with the atoms to which they areattached form an aryl, cycloalkyl, heterocyclyl, or heteroaryl ring.

In one embodiment, R^(1b) is selected from:

-   Y is S or O;-   R¹⁰ is hydrogen or alkyl; and-   R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each    independently selected from hydrogen, halo, amino, alkylamino,    alkyl, alkoxyl, cycloalkyl, and aryl.

In one embodiment, R¹⁰ is hydrogen or alkyl; and R¹¹, R¹², R¹³, R¹⁴,R¹⁵, R¹⁶, R¹⁷, R¹⁸, and R¹⁹ are each independently selected fromhydrogen, halo, and alkyl.

In one embodiment, R^(1b) is

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is(C₁-C₄)alkyl (e.g., methyl).

In one embodiment, R¹⁰ and R¹⁵ are each hydrogen.

In one embodiment, R¹² is hydrogen. In one embodiment, R¹² is halo(e.g., fluoro).

In one embodiment, R¹³ is hydrogen. In one embodiment, R¹³ is halo(e.g., fluoro or chloro).

In one embodiment, R¹⁴ is hydrogen. In one embodiment, R¹⁴ is halo(e.g., chloro).

In one embodiment, R^(1b) is

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is(C₁-C₄)alkyl (e.g. methyl).

In one embodiment, R¹⁰, R¹⁷, R¹⁸ and R¹⁹ are each hydrogen.

In one embodiment, R^(1b) is

In one embodiment, Y is O. In one embodiment, Y is S.

In one embodiment, R¹⁰, R¹¹, R¹⁷ and R¹⁸ are each hydrogen.

In one embodiment, R^(1b) is

In one embodiment, Y is S.

In one embodiment, R¹⁰, R¹¹, R¹⁷ and R¹⁹ are each hydrogen.

In one embodiment, R^(lb) is

In one embodiment, R¹¹ is hydrogen. In one embodiment, R¹¹ is(C₁-C₄)alkyl (e.g., methyl).

In one embodiment, R¹⁰, R¹², R¹³, R¹⁴ and R¹⁵ are each hydrogen.

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R^(1b) is represented by the following structure:

In one embodiment, R⁵ is hydrogen or alkyl; and R⁶, R⁸ and R⁹ are eachindependently selected from hydrogen, halo, amino, alkylamino, alkyl,alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁵ is hydrogen. In one embodiment, R⁵ is alkyl (e.g.,methyl or 2-(pyrrolidin-2,5-dionyl)ethane).

In one embodiment, R⁶ is hydrogen. In one embodiment, R⁹ is hydrogen. Inone embodiment, R⁸ is hydrogen. In one embodiment, R⁸ is (C₁-C₄)alkyl(e.g., methyl).

Specific examples include, but are not limited to, the followingcompounds:

In one embodiment, R^(1b) is represented by the following structure:

In one embodiment, R⁶, R⁸ and R⁹ are each independently selected fromhydrogen, halo, amino, alkylamino, alkyl, alkoxyl, cycloalkyl, and aryl.

In one embodiment, R⁶, R⁸ and R⁹ are each hydrogen.

Specific examples include, but are not limited to, the followingcompound:

In one embodiment, R^(1b) is selected from the following:

It should be noted that if there is a discrepancy between a depictedstructure and a chemical name given that structure, the depictedstructure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it or mixtures thereof. Where the compound providedherein contains an alkenyl or alkenylene group, the compound may existas one of or a mixture of geometric cis/trans (or Z/E) isomers. Wherestructural isomers are inter-convertible, the compound may exist as asingle tautomer or a mixture of tautomers. This can take the form ofproton tautomerism in the compound that contains, for example, an imino,keto, or oxime group; or so-called valence tautomerism in the compoundthat contains, for example, an aromatic moiety. It follows that a singlecompound may exhibit more than one type of isomerism.

The compounds provided herein may be enantiomerically pure ordiastereomerically pure, such as a single enantiomer or a singlediastereomer, or be stereoisomeric mixtures, such as a mixture ofenantiomers and/or diastereomers, e.g., a racemic or enantioenrichedmixture of two enantiomers; or a mixture of two or more diastereomers.In some instances, for compounds that undergo epimerization in vivo, oneof skill in the art will recognize that administration of a compound inits (R) form is equivalent to administration of the compound in its (S)form, and vice versa. Conventional techniques for thepreparation/isolation of individual enantiomers or diastereomers includesynthesis from a suitable optically pure precursor, asymmetric synthesisfrom achiral starting materials, or resolution of a stereomeric mixture,for example, by chiral chromatography, recrystallization, resolution,diastereomeric salt formation, or derivatization into diastereomericadducts followed by separation.

When the compound provided herein contains an acidic or basic moiety, itmay also be provided as a pharmaceutically acceptable salt (See, Bergeet al., J. Pharm. Sci. 1977, 66, 1-19; and “Handbook of PharmaceuticalSalts, Properties, and Use,” Stahl and Wermuth, Ed.; Wiley-VCH and VHCA,Zurich, 2002).

Suitable acids for use in the preparation of pharmaceutically acceptablesalts include, but are not limited to, acetic acid, 2,2-dichloroaceticacid, acylated amino acids, adipic acid, alginic acid, ascorbic acid,aspartic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, boric acid, camphoric acid, (+)-camphoric acid,camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid,caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid,cyclohexanesulfamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, D-gluconic acid, glucuronic acid, D-glucuronic acid,glutamic acid, L-glutamic acid, α-oxoglutaric acid, glycolic acid,hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid,isoethonic acid; (+)-L-lactic acid, (±)-DL-lactic acid, lactobionicacid, lauric acid, maleic acid, malic acid, (−)-L-malic acid, malonicacid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonicacid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,palmitic acid, pamoic acid, perchloric acid, phosphoric acid,pyroglutamic acid, pyroglutamic acid, L-pyroglutamic acid, saccharicacid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearicacid, succinic acid, sulfuric acid, tannic acid, tartaric acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid,undecylenic acid, and valeric acid.

Suitable bases for use in the preparation of pharmaceutically acceptablesalts, including, but not limited to, inorganic bases, such as magnesiumhydroxide, calcium hydroxide, potassium hydroxide, potassium carbonate,zinc hydroxide, sodium hydroxide, or ammonia; and organic bases, such asprimary, secondary, tertiary, and quaternary, aliphatic and aromaticamines, including L-arginine, benethamine, benzathine, choline, deanol,diethanolamine, diethylamine, dimethylamine, dipropylamine,diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine,ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine,1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine,methylamine, piperidine, piperazine, propylamine, pyrrolidine,1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline,isoquinoline, secondary amines, triethanolamine, trimethylamine,triethylamine, N-methyl-D-glucamine,2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine.

Unless otherwise specified, the term “compound” referred to herein, suchas, e.g., a compound of formula (I) is intended to encompass one or moreof the following, a stereoisomer or a mixture of two or morestereoisomers, a solid form (e.g., a crystal form or an amorphous form)or a mixture of two or more solid forms thereofthereof. In certainembodiments, the term “compound” referred to herein is intended toencompass a pharmaceutical acceptable form of the compound, includingbut not limited to, a free base, a stereoisomer or a mixture of two ormore stereoisomers, a solid form (e.g., a crystal form or an amorphousform) or a mixture of two or more solid forms.

The compound provided herein may also be provided as a prodrug, which isa functional derivative of the compound, for example, of Formula (I) andis readily convertible into the parent compound in vivo. Prodrugs areoften useful because, in some situations, they may be easier toadminister than the parent compound. They may, for instance, bebioavailable by oral administration whereas the parent compound is not.The prodrug may also have enhanced solubility in pharmaceuticalcompositions over the parent compound. A prodrug may be converted intothe parent drug by various mechanisms, including enzymatic processes andmetabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4,221-294; Morozowich et al. in “Design of Biopharmaceutical Propertiesthrough Prodrugs and Analogs,” Roche Ed., APHA Acad. Pharm. Sci. 1977;“Bioreversible Carriers in Drug in Drug Design, Theory and Application,”Roche Ed., APHA Acad. Pharm. Sci. 1987; “Design of Prodrugs,” Bundgaard,Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265-287;Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen etal., Pharm. Biotech. 1998, 11, 345-365; Gaignault et al., Pract. Med.Chem. 1996, 671-696; Asgharnejad in “Transport Processes inPharmaceutical Systems,” Amidon et al., Ed., Marcell Dekker, 185-218,2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15,143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209;Browne, Clin. Neuropharmacol. 1997, 20, 1-12; Bundgaard, Arch. Pharm.Chem. 1979, 86, 1-39; Bundgaard, Controlled Drug Delivery 1987, 17,179-96; Bundgaard, Adv. Drug Delivery Rev. 1992, 8, 1-38; Fleisher etal., Adv. Drug Delivery Rev. 1996, 19, 115-130; Fleisher et al., MethodsEnzymol. 1985, 112, 360-381; Farquhar et al., J. Pharm. Sci. 1983, 72,324-325; Freeman et al., J. Chem. Soc., Chem. Commun. 1991, 875-877;Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49-59; Gangwar et al.,Des. Biopharm. Prop. Prodrugs Analogs, 1977, 409-421; Nathwani and Wood,Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev.1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al.,Adv. Drug Delivery Rev. 1999, 39, 117-151; Taylor, Adv. Drug DeliveryRev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39,63-80; and Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

C. Methods of Treatment, Prevention, and/or Management

1. In Vivo Assays

In one embodiment, provided herein is a method of administering acompound provided herein, or a pharmaceutically acceptable salt orstereoisomer thereof, in a disease model that is known in the art. Inone embodiment, the disease model is an animal model. In one embodiment,provided herein is a method of administering a compound provided herein,or a pharmaceutically acceptable salt or stereoisomer thereof, in ananimal model that is predictive of efficacy in the treatment of certaindiseases in human. The method comprises administering a compoundprovided herein, or a pharmaceutically acceptable salt or stereoisomerthereof, in a subject. In one embodiment, the method comprisesadministering a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt or stereoisomer thereof,in a subject. In one embodiment, the method comprises treatment of atest subject (e.g., a mouse or rat) with a compound provided herein, ora pharmaceutically acceptable salt or stereoisomer thereof. In oneembodiment, the method comprises treatment of a test subject (e.g., amouse or rat) with a compound provided herein, or a pharmaceuticallyacceptable salt or stereoisomer thereof, as well as a referencecompound, either in separate animal groups (e.g., administer a referencecompound in a control group and administer a compound provided herein ina test group) or in the same animal group (e.g., as combinationtherapy). In one embodiment, the in vivo activity of the compoundprovided herein is dose dependent.

In one embodiment, the compounds provided herein are active in animalmodels of psychosis such as Pre-Pulse Inhibition (PPI) and PCP-inducedhyperlocomotion. These two models have been used in the development ofseveral antipsychotics, including olanzapine (Bakshi and Geyer,Psychopharmacology 1995, 122, 198-201) and quetapine (Swedlow et al., J.Pharm. Exp. Ther., 1996, 279, 1290-99), and are predictive of efficacyin human psychotic patients. In one embodiment, compounds that areactive in in vivo models of psychosis are further optimized to improvethe potency in the in vivo assays and drug-like properties such as,e.g., solubility and lipophilicity. Given the exact molecular basis ofcertain diseases such as schizophrenia are poorly understood, thisapproach allows the use of predictive and well-validated animial modelsto develop compounds with established efficacy without focusing onspecific molecular targets that may or may not translate to humanefficacy in the clinic.

2. Treatment, Prevention, and/or Management

In one embodiment, provided herein is a method of treating, preventing,and/or managing various disorders, including, but not limited to,neurological disorders. In one embodiment, provided herein is a methodof treating, preventing, and/or managing one or more symptoms of aneurological disorder. In one embodiment, the method comprisesadministering to a subject (e.g., human) a therapeutically orprophylactically effective amount of a composition or a compoundprovided herein or a pharmaceutically acceptable salt or stereoisomerthereof. In one embodiment, the subject is a human. In one embodiment,the subject is an animal. In one embodiment, the compounds providedherein are highly brain penetrable in the subject. In certainembodiments, the efficacious concentration of a compound provided hereinis less than 10 nM, less than 100 nM, less than 1 μM, less than 10 μM,less than 100 μM, or less than 1 mM. In one embodiment, a compound'sactivity may be assessed in various art-recognized animal models asdescribed herein elsewhere or known in the literature.

In one embodiment, without being limited by a particular theory, thetreatment, prevention, and/or management is done by administering acompound provided herein that has shown in vivo efficacy in an animalmodel predictive of antipsychotic activity in humans. The phenotypicapproach to develop antipsychotics has been used in psychopharmacology,with the antipsychotic chlorpromazine developed in this way. Thephenotypic approach may also offer advantages over compounds developedby traditional in vitro based drug discovery approach, because thecompounds developed using the phenotypic approach have establishedpharmaceutical properties and in vivo activity, rather than activitytoward a given molecular target, which may be less predictive and leadto attrition at later stages of, for example, clinical development.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a neurological disorder, including schizophrenia,schizophrenia spectrum disorder, acute schizophrenia, chronicschizophrenia, NOS schizophrenia, schizoid personality disorder,schizotypal personality disorder, delusional disorder, psychosis,psychotic disorder, brief psychotic disorder, shared psychotic disorder,psychotic disorder due to a general medical condition, drug-inducedpsychosis (e.g., cocaine, alcohol, amphetamine), psychoaffectivedisorder, aggression, delirium, Parkinson's psychosis, excitativepsychosis, Tourette's syndrome, organic or NOS psychosis, seizure,agitation, post-traumatic stress disorder, behavior disorder,neurodegenerative disease, Alzheimer's disease, Parkinson's disease,dyskinesias, Huntington's disease, dementia, mood disorder, anxiety,affective disorders (e.g., depression, e.g., major depressive disorderand dysthymia; bipolar disorder, e.g., biopolar depressive disorder;manic disorder; seasonal affective disorder; and attention deficitdisorder (ADD) and attention deficit hyperactivity disorder (ADHD)),obsessive-compulsive disorder, vertigo, epilepsy, pain (e.g.,neuropathic pain, sensitization accompanying neuropathic pain, andinflammatory pain), fibromyalgia, migraine, cognitive impairment,cognitive impairment associated with schizophrenia (CIAS), movementdisorder, restless leg syndrome (RLS), multiple sclerosis, sleepdisorder, sleep apnea, narcolepsy, excessive daytime sleepiness, jetlag, drowsy side effect of medications, insomnia, substance abuse ordependency (e.g., nicotine, cocaine), addiction, eating disorder, sexualdysfunction, hypertension, emesis, Lesche-Nyhane disease, Wilson'sdisease, autism, Huntington's chorea, and premenstrual dysphoria,comprising administering to a subject an effective amount of a compoundprovided herein, or a pharmaceutically acceptable salt or stereoisomerthereof.

In one embodiment, provided herein is a method of treating, preventing,and/or managing a disorder related to psychosis, schizophrenia, ADHD,mood disorder or affective disorder such as depression and anxiety,comprising administering to a subject an effective amount of a compoundprovided herein. For example, without being limited by a particulartheory, the compounds provided herein may improve the gating deficits ofDBA/2 mice seen in the pre-pulse inhibition (PPI) test and reverse themethamphe-tamine-induced hyperlocomotor activity. Without being limitedto a particular theory, the compounds provided herein may: 1) reversethe amphetamine-induced hyper-locomotor activity; 2) be useful asantipsychotic agents and dosed sparing; 3) improve attention andmodulate impulsivity; 4) improve learning parameters in ADHD; 5) enhancelearning ability and reduce anxiety in behavioral tests; and/or 6) havean anti-depressant effect.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder related to cognitive impairments,such as Alzheimer's disease, Parkinson's disease, schizophrenia,cognitive impairment associated with schizophrenia (CIAS), and attentiondeficit hyperactivity disorder (ADHD), and the like, comprisingadministering to a subject an effective amount of a compound providedherein. For example, without being limited by a particular theory, thecompounds provided herein may have pro-cognitive effects, such aspassive avoidance, novel object recognition, social recognition, andattention-set shifting. Further, without being limited by a particulartheory, the compounds provided herein may improve social memory,increase the acquisition of an environment, and reversescopolamine-induced deficits. The compounds provided herein may alsoreverse scopolamine-induced deficits in a passive avoidance memory test.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder associated with excessive daytimesleepiness, such as, narcolepsy, Parkinson's disease, multiplesclerosis, shift workers, jet lag, relief of side effects of othermedications, and the like, comprising administering to a subject aneffective amount of a compound provided herein. For example, withoutbeing limited by a particular theory, the compounds provided herein mayhave wake promoting effects.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a sleeping disorder, such as insomnia,comprising administering to a subject an effective amount of a compoundprovided herein. For example, without being limited by a particulartheory, the compounds provided herein may improve wakefulness and leadto an improved sleep pattern, and therefore the compounds providedherein may be useful in treating insomnia.

In another embodiment, provided herein is a method of treating,preventing, and/or managing substance abuse, comprising administering toa subject an effective amount of a compound provided herein. Forexample, without being limited by a particular theory, the compoundsprovided herein may alter methamphetamine self-administration in rats,and therefore the compounds provided herein may ameliorate the cravingfor addictive drugs.

In another embodiment, provided herein is a method of using thecompounds provided herein as psycho-stimulants, which may lack the abuseliabilities generally associated with other classes ofpsycho-stimulants. Without being limited by a particular theory, thecompounds provided herein may increase the levels of histamine,dopamine, norepinephrine, and/or acetylcholine in the prefrontalcortical area, which is consistent with their pro-cognitive effects andtheir wake promoting effects seen in animal models. For example, thecompounds provided herein may increase dopamine in the frontal cortexbut not the striatum. The compounds provided herein may not induceincreased locomotor activity or sensitization that is associated withother psycho-stimulus.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a disorder such as seizure, epilepsy,vertigo, and pain, comprising administering to a subject an effectiveamount of a compound provided herein. For example, without being limitedby a particular theory, the compounds provided herein may be protectiveagainst pentylene-tetrazole (PTZ) and electrical-induced seizures. Thecompounds provided herein may increase the seizure threshold in humans.The compounds provided herein may decrease electrical discharge fromafferent neurons in an inner ear preparation. Further, without beinglimited by a particular theory, the compounds provided herein mayincrease the threshold for neuropathic pain, which is shown in modelssuch as the chronic constriction injure (CCI) model, herpesvirus-induced model, and capsaicin-induced allodynia model. Therefore,in some embodiments, the compounds provided herein are employed fortheir analgesic effects to treat, prevent, and/or manage disordersinvolving pain and the sensitization that accompanies many neuropathicpain disorders.

In another embodiment, provided herein is a method of treating,preventing, and/or managing a movement disorder, such as Parkinson'sdisease, restless leg syndrome (RLS), and Huntington's disease,comprising administering to a subject an effective amount of a compoundprovided herein.

In some embodiments, a compound provided herein is active in at leastone model, which can be used to measure the activity of the compound andestimate the efficacy in treating a neurological disorder. For example,when the model is for psychosis (e.g., PCP Hyperactivity Model orPrepulse Inhibition of Startle Model), a compound is active when thecompound reduces PCP induced hyperactivity in mice by a statisticallysignicant amount compared to a vehicle, or when the compound reversesthe disruption of prepulse inhibition (PPI) induced by PCP in mice.

In other embodiments, provided herein is a method of effecting atherapeutic effect as described herein elsewhere. The method comprisesadministering to a subject (e.g., a mammal) a therapeutically effectiveamount of a compound or composition provided herein. The particulartherapeutic effects may be measured using any model system known in theart and described herein, such as those involving an animal model of adisease.

In some embodiments, the neurological disorder is: depression (e.g.,major depressive disorder or dysthymia); bipolar disorder, seasonalaffective disorder; cognitive deficit; fibromyalgia; pain (e.g.,neuropathic pain); sleep related disorder (e.g., sleep apnea, insomnia,narcolepsy, cataplexy) including those sleep disorders which areproduced by psychiatric conditions; chronic fatigue syndrome; attentiondeficit disorder (ADD); attention deficit hyperactivity disorder (ADHD);restless leg syndrome; schizophrenia; anxieties (e.g., general anxietydisorder, social anxiety disorder, panic disorder); obsessive compulsivedisorder; post-traumatic stress disorder; seasonal affective disorder(SAD); premenstrual dysphoria; post-menopausal vasomotor symptoms (e.g.,hot flashes, night sweats); neurodegenerative disease (e.g., Parkinson'sdisease, Alzheimer's disease and amyotrophic lateral sclerosis); manicdisorder; dysthymic disorder; cyclothymic disorder; obesity; andsubstance abuse or dependency (e.g., cocaine addiction, nicotineaddiction). In another embodiment, the compounds provided herein areuseful to treat, prevent, and/or manage two or moreconditions/disorders, which are co-morbid, such as psychosis anddepression.

Neurological disorders may also include cerebral function disorders,including without limitation, senile dementia, Alzheimer's typedementia, cognition, memory loss, amnesia/amnestic syndrome, epilepsy,disturbances of consciousness, coma, lowering of attention, speechdisorder, Lennox syndrome, autism, and hyperkinetic syndrome.

Neuropathic pain includes, without limitation, post herpetic (orpost-shingles) neuralgia, reflex sympathetic dystrophy/causalgia ornerve trauma, phantom limb pain, carpal tunnel syndrome, and peripheralneuropathy (such as diabetic neuropathy or neuropathy arising fromchronic alcohol use).

Other exemplary diseases and conditions that may be treated, prevented,and/or managed using the methods, compounds, and/or compositionsprovided herein include, but are not limited to: obesity; migraine ormigraine headache; and sexual dysfunction, in men or women, includingwithout limitation sexual dysfunction caused by psychological and/orphysiological factors, erectile dysfunction, premature ejaculation,vaginal dryness, lack of sexual excitement, inability to obtain orgasm,and psycho-sexual dysfunction, including without limitation, inhibitedsexual desire, inhibited sexual excitement, inhibited female orgasm,inhibited male orgasm, functional dyspareunia, functional vaginismus,and atypical psychosexual dysfunction.

In one embodiment, the neurological disorder is excessive daytimesleepiness. In another embodiment, the neurological disorder is acognitive impairment. In another embodiment, the neurological disorderis a mood disorder. In another embodiment, the neurological disorder isan affective disorder. In another embodiment, the neurological disorderis a movement disorder. In another embodiment, the neurological disorderis schizophrenia. In another embodiment, the neurological disorder is anattention disorder. In another embodiment, the neurological disorder isan anxiety disorder. In another embodiment, the neurological disorder isseizure. In another embodiment, the neurological disorder is psychosis.In another embodiment, the neurological disorder is epilepsy. In anotherembodiment, the neurological disorder is vertigo. In another embodiment,the neurological disorder is pain. In another embodiment, theneurological disorder is neuropathic pain. In another embodiment, theneuropathic pain is diabetic neuropathy.

In one embodiment, the neurological disorder is a neurodegenerativedisease. In one embodiment, the neurodegenerative disease is Parkinson'sdisease. In another embodiment, the neurodegenerative disorder isAlzheimer's disease.

In one embodiment, the compounds described herein treat, prevent, and/ormanage a neurological disorder of the central nervous system, withoutcausing addiction to said compounds.

Any suitable route of administration can be employed for providing thepatient with a therapeutically or prophylactically effective dose of anactive ingredient. For example, oral, mucosal (e.g., nasal, sublingual,buccal, rectal, vaginal), parenteral (e.g., intravenous, intramuscular),transdermal, and subcutaneous routes can be employed. Exemplary routesof administration include oral, transdermal, and mucosal. Suitabledosage forms for such routes include, but are not limited to,transdermal patches, ophthalmic solutions, sprays, and aerosols.Transdermal compositions can also take the form of creams, lotions,and/or emulsions, which can be included in an appropriate adhesive forapplication to the skin or can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose. An exemplary transdermal dosage form is a “reservoir type” or“matrix type” patch, which is applied to the skin and worn for aspecific period of time to permit the penetration of a desired amount ofactive ingredient. The patch can be replaced with a fresh patch whennecessary to provide constant administration of the active ingredient tothe patient.

The amount to be administered to a patient to treat, prevent, and/ormanage the disorders described herein will depend upon a variety offactors including the activity of the particular compound employed, orthe ester, salt or amide thereof, the route of administration, the timeof administration, the rate of excretion or metabolism of the particularcompound being employed, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount required. For example, thephysician or veterinarian could start doses of the compounds employed atlevels lower than that required in order to achieve the desiredtherapeutic effect and gradually increase the dosage until the desiredeffect is achieved.

In general, a suitable daily dose of a compound provided herein will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic or prophylactic effect. Such an effective dosewill generally depend upon the factors described above. Generally, oral,intravenous, intracerebroventricular and subcutaneous doses of thecompounds provided herein for a patient will range from about 0.005 mgper kilogram to about 5 mg per kilogram of body weight per day. In oneembodiment, the oral dose of a compound provided herein will range fromabout 10 mg to about 300 mg per day. In another embodiment, the oraldose of a compound provided herein will range from about 20 mg to about250 mg per day. In another embodiment, the oral dose of a compoundprovided herein will range from about 100 mg to about 300 mg per day. Inanother embodiment, the oral dose of a compound provided herein willrange from about 10 mg to about 100 mg per day. In another embodiment,the oral dose of a compound provided herein will range from about 25 mgto about 50 mg per day. In another embodiment, the oral dose of acompound provided herein will range from about 50 mg to about 200 mg perday. Each of the above-recited dosage ranges may be formulated as asingle or multiple unit dosage formulations.

In some embodiments, the compounds disclosed herein may be used in acombination treatment with one or more second active agents to treat,prevent, and/or manage disorders described herein. In one embodiment,the one or more second active agents are selected from antidepressants,agents useful in the treatment of Parkinson's disease andantipsychotics. Exemplary antipsychotics include, but are not limited toatypical antipsychotics such as amisulpride, aripiprazole, asenapine,blonanserin, clotiapine, clozapine, iloperidone, lurasidone,mosapramine, olanzapine, paliperidone, perospirone, quetiapine,remoxipride, risperidone, sertindole, sulpiride, ziprasidone, andzotepine. Exemplary antidepressants include, but are not limited tocitalopram, excitalopram, fluoxetine, fluvoxamine, paroxetine,sertraline, vilazodone, desvenlafaxine, duloxetine, milnacipran,vanlafaxine, mianserin, mirtazapine, atomoxetine, mazindol, reboxetine,viloxazine, bupropion, agomelatine, amitriptyline, clomipramine,doxepin, imipramine, timipramine, desipramine, nortriptyline,protriptyline, isocarboxazid, moclobemide, phenelzine, selegiline,tranylcypromine, buspirone, gepirone, nefazodone, tandospirone andtrazodone. Exemplary treatments for Parkinson's disease include, but arenot limited to carbidopa, levodopa, entacapone, bromocriptine,pergolide, pramipexole, ropinirole, rotogotine, tolcapone, selegiline,rasagiline, benzotropine, trihexylphenidyl and amantadine.

3. Pharmaceutical Compositions and Dosage Forms

Pharmaceutical compositions can be used in the preparation ofindividual, single unit dosage forms. Pharmaceutical compositions anddosage forms provided herein comprise a compound provided herein, or apharmaceutically acceptable salt, stereoisomer, clathrate, or prodrugthereof. Pharmaceutical compositions and dosage forms can furthercomprise one or more excipients.

Pharmaceutical compositions and dosage forms provided herein can alsocomprise one or more additional active ingredients. Examples of optionalsecond, or additional, active ingredients are also disclosed herein.

Single unit dosage forms provided herein are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintra-arterial), topical (e.g., eye drops or other ophthalmicpreparations), transdermal or transcutaneous administration to apatient. Examples of dosage forms include, but are not limited to:tablets; caplets; capsules, such as soft elastic gelatin capsules;cachets; troches; lozenges; dispersions; suppositories; powders;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; eye drops or other ophthalmic preparations suitable fortopical administration; and sterile solids (e.g., crystalline oramorphous solids) that can be reconstituted to provide liquid dosageforms suitable for parenteral administration to a patient.

The composition, shape, and type of dosage forms will typically varydepending on their use. For example, a dosage form used in the acutetreatment of a disease may contain larger amounts of one or more of theactive ingredients it comprises than a dosage form used in the chronictreatment of the same disease. Similarly, a parenteral dosage form maycontain smaller amounts of one or more of the active ingredients itcomprises than an oral dosage form used to treat the same disease. Theseand other ways in which specific dosage forms are used will vary fromone another and will be readily apparent to those skilled in the art.See, e.g., Remington's Pharmaceutical Sciences, 18th Ed., MackPublishing, Easton Pa. (1990).

In one embodiment, pharmaceutical compositions and dosage forms compriseone or more excipients. Suitable excipients are well known to thoseskilled in the art of pharmacy, and non-limiting examples of suitableexcipients are provided herein. Whether a particular excipient issuitable for incorporation into a pharmaceutical composition or dosageform depends on a variety of factors well known in the art including,but not limited to, the way in which the dosage form will beadministered to a patient. For example, oral dosage forms such astablets may contain excipients not suited for use in parenteral dosageforms. The suitability of a particular excipient may also depend on thespecific active ingredients in the dosage form. For example, thedecomposition of some active ingredients may be accelerated by someexcipients such as lactose, or when exposed to water. Active ingredientsthat comprise primary or secondary amines are particularly susceptibleto such accelerated decomposition. Consequently, provided arepharmaceutical compositions and dosage forms that contain little, ifany, lactose other mono- or disaccharides. As used herein, the term“lactose-free” means that the amount of lactose present, if any, isinsufficient to substantially increase the degradation rate of an activeingredient.

Lactose-free compositions can comprise excipients that are well known inthe art and are listed, for example, in the U.S. Pharmacopeia (USP)25-NF20 (2002). In general, lactose-free compositions comprise activeingredients, a binder/filler, and a lubricant in pharmaceuticallycompatible and pharmaceutically acceptable amounts. In one embodiment,lactose-free dosage forms comprise active ingredients, microcrystallinecellulose, pre-gelatinized starch, and/or magnesium stearate.

Also provided are anhydrous pharmaceutical compositions and dosage formscomprising active ingredients, since water can facilitate thedegradation of some compounds. For example, the addition of water (e.g.,5%) is widely accepted in the pharmaceutical arts as a means ofsimulating long-term storage in order to determine characteristics suchas shelf-life or the stability of formulations over time. See, e.g.,Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed.,Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect, water and heataccelerate the decomposition of some compounds. Thus, the effect ofwater on a formulation can be of great significance since moistureand/or humidity are commonly encountered during manufacture, handling,packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms can be preparedusing anhydrous or low moisture containing ingredients and low moistureor low humidity conditions. Pharmaceutical compositions and dosage formsthat comprise lactose and at least one active ingredient that comprisesa primary or secondary amine are preferably anhydrous if substantialcontact with moisture and/or humidity during manufacturing, packaging,and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are, in one embodiment, packaged using materials known toprevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastics, unit dose containers(e.g., vials), blister packs, and strip packs.

Also provided are pharmaceutical compositions and dosage forms thatcomprise one or more compounds that reduce the rate by which an activeingredient will decompose. Such compounds, which are referred to hereinas “stabilizers,” include, but are not limited to, antioxidants such asascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. In one embodiment, dosage forms comprise a compoundprovided herein in an amount of from about 0.10 to about 500 mg. Inother embodiments, dosage forms comprise a compound provided herein inan amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50,100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.

In other embodiments, dosage forms comprise a second active ingredientin an amount of 1 to about 1000 mg, from about 5 to about 500 mg, fromabout 10 to about 350 mg, or from about 50 to about 200 mg. Of course,the specific amount of the second active agent will depend on thespecific agent used, the diseases or disorders being treated or managed,and the amount(s) of a compound provided herein, and any optionaladditional active agents concurrently administered to the patient.

In one embodiment, pharmaceutical compositions and dosage formsdescribed herein include one or more second active agents to treat,prevent, and/or manage disorders described herein. In one embodiment,the one or more second active agents are selected from antidepressants,agents useful in the treatment of Parkinson's disease andantipsychotics.

(a) Oral Dosage Forms

Pharmaceutical compositions that are suitable for oral administrationcan be provided as discrete dosage forms, such as, but not limited to,tablets (e.g., chewable tablets), caplets, capsules, and liquids (e.g.,flavored syrups). Such dosage forms contain predetermined amounts ofactive ingredients, and may be prepared by methods of pharmacy wellknown to those skilled in the art. See generally, Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

Oral dosage forms provided herein are prepared by combining the activeingredients in an intimate admixture with at least one excipientaccording to conventional pharmaceutical compounding techniques.Excipients can take a wide variety of forms depending on the form ofpreparation desired for administration. For example, excipients suitablefor use in oral liquid or aerosol dosage forms include, but are notlimited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

In one embodiment, oral dosage forms are tablets or capsules, in whichcase solid excipients are employed. In another embodiment, tablets canbe coated by standard aqueous or non-aqueous techniques. Such dosageforms can be prepared by any of the methods of pharmacy. In general,pharmaceutical compositions and dosage forms are prepared by uniformlyand intimately admixing the active ingredients with liquid carriers,finely divided solid carriers, or both, and then shaping the productinto the desired presentation if necessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms providedherein include, but are not limited to, binders, fillers, disintegrants,and lubricants. Binders suitable for use in pharmaceutical compositionsand dosage forms include, but are not limited to, corn starch, potatostarch, or other starches, gelatin, natural and synthetic gums such asacacia, sodium alginate, alginic acid, other alginates, powderedtragacanth, guar gum, cellulose and its derivatives (e.g., ethylcellulose, cellulose acetate, carboxymethyl cellulose calcium, sodiumcarboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose,pre-gelatinized starch, hydroxypropyl methyl cellulose, (e.g., Nos.2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Aspecific example of a binder is a mixture of microcrystalline celluloseand sodium carboxymethyl cellulose sold as AVICEL RC-581. Suitableanhydrous or low moisture excipients or additives include AVICEL-PH-103™and Starch 1500 LM.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms provided herein include, but are not limited to, talc,calcium carbonate (e.g., granules or powder), microcrystallinecellulose, powdered cellulose, dextrates, kaolin, mannitol, silicicacid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.The binder or filler in pharmaceutical compositions is, in oneembodiment, present in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Disintegrants may be used in the compositions to provide tablets thatdisintegrate when exposed to an aqueous environment. Tablets thatcontain too much disintegrant may disintegrate in storage, while thosethat contain too little may not disintegrate at a desired rate or underthe desired conditions. Thus, a sufficient amount of disintegrant thatis neither too much nor too little to detrimentally alter the release ofthe active ingredients may be used to form solid oral dosage forms. Theamount of disintegrant used varies based upon the type of formulation,and is readily discernible to those of ordinary skill in the art. In oneembodiment, pharmaceutical compositions comprise from about 0.5 to about15 weight percent of disintegrant, or from about 1 to about 5 weightpercent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, agar-agar, alginic acid, calciumcarbonate, microcrystalline cellulose, croscarmellose sodium,crospovidone, polacrilin potassium, sodium starch glycolate, potato ortapioca starch, other starches, pre-gelatinized starch, other starches,clays, other algins, other celluloses, gums, and mixtures thereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms include, but are not limited to, calcium stearate, magnesiumstearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol,polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate,talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zincstearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.Additional lubricants include, for example, a syloid silica gel(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), acoagulated aerosol of synthetic silica (marketed by Degussa Co. ofPlano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants may be used in an amount of less than about 1 weight percentof the pharmaceutical compositions or dosage forms into which they areincorporated.

In one embodiment, a solid oral dosage form comprises a compoundprovided herein, and optional excipients, such as anhydrous lactose,microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,colloidal anhydrous silica, and gelatin.

(b) Controlled Release Dosage Forms

Active ingredients provided herein can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active agents provided herein. In one embodiment, provided aresingle unit dosage forms suitable for oral administration such as, butnot limited to, tablets, capsules, gelcaps, and caplets that are adaptedfor controlled-release.

In one embodiment, controlled-release pharmaceutical products improvedrug therapy over that achieved by their non-controlled counterparts. Inanother embodiment, the use of a controlled-release preparation inmedical treatment is characterized by a minimum of drug substance beingemployed to cure or control the condition in a minimum amount of time.Advantages of controlled-release formulations include extended activityof the drug, reduced dosage frequency, and increased patient compliance.In addition, controlled-release formulations can be used to affect thetime of onset of action or other characteristics, such as blood levelsof the drug, and can thus affect the occurrence of side (e.g., adverse)effects.

In another embodiment, the controlled-release formulations are designedto initially release an amount of drug (active ingredient) that promptlyproduces the desired therapeutic or prophylactic effect, and graduallyand continually release of other amounts of drug to maintain this levelof therapeutic or prophylactic effect over an extended period of time.In one embodiment, in order to maintain a constant level of drug in thebody, the drug can be released from the dosage form at a rate that willreplace the amount of drug being metabolized and excreted from the body.Controlled-release of an active ingredient can be stimulated by variousconditions including, but not limited to, pH, temperature, enzymes,water, or other physiological conditions or compounds.

(c) Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intra-arterial. In someembodiments, administration of a parenteral dosage form bypassespatients' natural defenses against contaminants, and thus, in theseembodiments, parenteral dosage forms are sterile or capable of beingsterilized prior to administration to a patient. Examples of parenteraldosage forms include, but are not limited to, solutions ready forinjection, dry products ready to be dissolved or suspended in apharmaceutically acceptable vehicle for injection, suspensions ready forinjection, and emulsions.

Suitable vehicles that can be used to provide parenteral dosage formsare well known to those skilled in the art. Examples include, but arenot limited to: Water for Injection USP; aqueous vehicles such as, butnot limited to, Sodium Chloride Injection, Ringer's Injection, DextroseInjection, Dextrose and Sodium Chloride Injection, and Lactated Ringer'sInjection; water-miscible vehicles such as, but not limited to, ethylalcohol, polyethylene glycol, and polypropylene glycol; and non-aqueousvehicles such as, but not limited to, corn oil, cottonseed oil, peanutoil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms. For example, cyclodextrin and its derivativescan be used to increase the solubility of a compound provided herein.See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein byreference.

(d) Topical and Mucosal Dosage Forms

Topical and mucosal dosage forms provided herein include, but are notlimited to, sprays, aerosols, solutions, emulsions, suspensions, eyedrops or other ophthalmic preparations, or other forms known to one ofskill in the art. See, e.g., Remington's The Science and Practice ofPharmacy, 21st Ed., Lippincott Williams & Wilkins (2005); andIntroduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,Philadelphia (1985). Dosage forms suitable for treating mucosal tissueswithin the oral cavity can be formulated as mouthwashes or as oral gels.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide topical and mucosal dosage forms encompassedherein are well known to those skilled in the pharmaceutical arts, anddepend on the particular tissue to which a given pharmaceuticalcomposition or dosage form will be applied. In one embodiment,excipients include, but are not limited to, water, acetone, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof to formsolutions, emulsions or gels, which are non-toxic and pharmaceuticallyacceptable. Moisturizers or humectants can also be added topharmaceutical compositions and dosage forms. Examples of additionalingredients are well known in the art. See, e.g., Remington's TheScience and Practice of Pharmacy, 21st Ed., Lippincott Williams &Wilkins (2005).

The pH of a pharmaceutical composition or dosage form may also beadjusted to improve delivery of one or more active ingredients. Also,the polarity of a solvent carrier, its ionic strength, or tonicity canbe adjusted to improve delivery. Compounds such as stearates can also beadded to pharmaceutical compositions or dosage forms to alter thehydrophilicity or lipophilicity of one or more active ingredients so asto improve delivery. In other embodiments, stearates can serve as alipid vehicle for the formulation, as an emulsifying agent orsurfactant, or as a delivery-enhancing or penetration-enhancing agent.In other embodiments, salts, solvates, prodrugs, clathrates, orstereoisomers of the active ingredients can be used to further adjustthe properties of the resulting composition.

4. Kits

In one embodiment, active ingredients provided herein are notadministered to a patient at the same time or by the same route ofadministration. In another embodiment, provided are kits which cansimplify the administration of appropriate amounts of activeingredients.

In one embodiment, a kit comprises a dosage form of a compound providedherein. Kits can further comprise one or more second active ingredientsas described herein, or a pharmacologically active mutant or derivativethereof, or a combination thereof.

In other embodiments, kits can further comprise devices that are used toadminister the active ingredients. Examples of such devices include, butare not limited to, syringes, drip bags, patches, and inhalers.

Kits can further comprise cells or blood for transplantation as well aspharmaceutically acceptable vehicles that can be used to administer oneor more active ingredients. For example, if an active ingredient isprovided in a solid form that must be reconstituted for parenteraladministration, the kit can comprise a sealed container of a suitablevehicle in which the active ingredient can be dissolved to form aparticulate-free sterile solution that is suitable for parenteraladministration. Examples of pharmaceutically acceptable vehiclesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

V. EXAMPLES

Certain embodiments are illustrated by the following non-limitingexamples.

A. General Procedures for Compound Synthesis

In the examples below, unless otherwise indicated, all temperatures areset forth in degrees Celsius and all parts and percentages are byweight. Reagents may be purchased from commercial suppliers, such asSigma-Aldrich® Chemical Company, and may be used without furtherpurification unless otherwise indicated. Reagents may also be preparedfollowing standard literature procedures known to those skilled in theart. Solvents may be purchased from Sigma-Aldrich® in Sure-Seal® bottlesand used as received. All solvents may be purified using standardmethods known to those skilled in the art, unless otherwise indicated.

The reactions set forth below were done generally at ambienttemperature, unless otherwise indicated. Unless otherwise specified,generally the reaction flasks were fitted with rubber septa forintroduction of substrates and reagents via syringe. Analytical thinlayer chromatography (TLC) was performed using glass-backed silica gelpre-coated plates and eluted with appropriate solvent ratios (v/v).Reactions were assayed by TLC or LCMS, and terminated as judged by theconsumption of starting material. Visualization of the TLC plates wasdone with UV light (254 wavelength) or with an appropriate TLCvisualizing solvent, such as basic aqueous KMnO₄ solution activated withheat. Flash column chromatography (see, e.g., Still et al., J. Org.Chem., 43: 2923 (1978)) was performed using, for example, silica gel 60or various MPLC systems (such as Biotage® or ISCO® separation systems).

The compound structures in the examples below were confirmed by one ormore of the following methods: proton nuclear magnetic resonancespectroscopy, mass spectroscopy, elemental microanalysis, and meltingpoint. Proton nuclear magnetic resonance (¹H NMR) spectra weredetermined using a NMR spectrometer operating at a certain fieldstrength. Chemical shifts are reported in parts per million (ppm, δ)downfield from an internal standard, such as TMS. Alternatively, ¹H NMRspectra were referenced to signals from residual protons in deuteratedsolvents, for example, as follows: CDCl₃=7.25 ppm; DMSO-d₆=2.49 ppm;C₆D₆=7.16 ppm; CD₃OD=3.30 ppm. Peak multiplicities are designated, forexample, as follows: s, singlet; d, doublet; dd, doublet of doublets; t,triplet; dt, doublet of triplets; q, quartet; br, broadened; and m,multiplet. Coupling constants are given in Hertz (Hz). Mass spectra (MS)data were obtained using a mass spectrometer with APCI or ESIionization.

1. 6-(2-fluorobenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine

(a) 6-(2-fluorobenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine

2-Fluorobenzo[b]thiophene (304 mg, 2 mmol) and pyrimidine (320 mg, 4mmol) were dissolved in TFA (1.0 mL) and the resulting mixture washeated at 120° C. in the microwave reactor for 10 minutes. After coolingto rt, the reaction mixture was poured into water and extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine(3×50 mL) and dried over anhydrous Na₂SO₄. After filtration, thesolution was concentrated to give the crude title compound. It was useddirectly without further purification.

(b) tert-butyl6-(2-fluorobenzo[b]thiophen-3-yl)pyrimidine-1(6H)-carboxylate

A solution of 6-(2-fluorobenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine inwater was treated with Na₂CO₃ until pH reached 9. A solution of Boc₂O indry EtOAc (20 mL) was then added dropwise. After the starting materialwas consumed completely as shown by TLC, the reaction mixture wasextracted with EtOAc (3×50 mL), washed with brine (3×50 mL), and driedover anhydrous Na₂SO₄. After filtration and concentration, the crudeproduct was purified by column chromatography to give the titlecompound.

(c) HCl salt of tert-butyl6-(2-fluorobenzo[b]thiophen-3-yl)pyrimidine-1(6H)

A solution of tert-butyl6-(2-fluorobenzo[b]thiophen-3-yl)pyrimidine-1(6H) in Et₂O was treatedwith gaseous HCl at 0° C. for 10 minutes. The precipitated solid wascollected by vacuum filtration and dried to give the desired product.

2. 6-(2,5-diethylthiophen-3-yl)-1-methyl-1,6-dihydropyrimidine and4-(2,5-diethylthiophen-3-yl)-1-methyl-1,4-dihydropyrimidine

(a) 6-(2,5-diethylthiophen-3-yl)-1-methyl-1,6-dihydropyrimidine and4-(2,5-diethylthiophen-3-yl)-1-methyl-1,4-dihydropyrimidine

2,5-Diethylthiophene (280 mg, 2 mmol) and 1-methylpyrimidin-1-ium iodide(888 mg, 4 mmol) was dissolved in TFA (1.0 mL) and the mixture washeated at 120° C. in the microwave reactor for 10 minutes. After coolingto room temperature, the reaction mixture was poured into water andextracted with EtOAc (3×50 mL). The combined organic layers were washedwith brine (3×50 mL) and dried over anhydrous Na₂SO₄. After filtrationand concentration, the crude product was purified by preparative HPLC togive the title compound.

(b) Preparation of HCl Salt

A solution of above product in Et₂O was treated with gaseous HCl at 0°C. for 10 minutes. The precipitated solid was collected by vacuumfiltration and dried to give the desired product.

3. 6-(2,5-difluorobenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine

(a) 6-(2,5-difluorobenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine

2,5-difluorobenzo[b]thiophene (340 mg, 2 mmol) and pyrimidine (320 mg, 4mmol) were dissolved in TFA (1.0 mL) and the resulting mixture was putin the ultrasonic reactor for 4 hours. The reaction mixture was thenpoured into water and extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine (3×50 mL) and dried over anhydrousNa₂SO₄. After filtration, the solution was concentrated to give thecrude title compound.

4. Generic ThiopheneSynthesis6-(2-phenylbenzo[b]thiophen-3-yl)-1,6-dihydropyrimidine

(a) 2-bromobenzo[b]thiophene

To a solution of benzo[b]thiophene (1.34 g, 10 mmol) in AcOH (10 mL) andDCM (25 mL) was added NBS (1.78 g, 10 mmol) in portions. After stirringovernight at room temperature, the reaction mixture was treated withNa₂SO₃ and water, followed by extraction with EtOAc. The combinedorganic layers were washed with brine and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound

(b) 2-phenylbenzo[b]thiophene

A 100 mL round-bottomed flask was charged with 2-bromobenzo[b]thiophene(1.06 g, 5 mmol), phenylboronic acid (1.22 g, 10 mmol), PPh₃ (265 mg, 1mmol) and Pd(OAc)₂ (224 mg, 1 mmol) in dioxide (50 mL) under nitrogen atroom temperature. After stirring for 30 minutes, Na₂CO₃ (159 mg, 7.5mmol) and H₂O (10 mL) were added. The resulting mixture was heated atreflux for 3 h. After cooling to rt, the reaction mixture was pouredinto water and extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (3×50 mL) and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound.

5. 3-chloro-2,5-dimethylthiophene

(a) 3-chloro-2,5-dimethylthiophene

To a solution of 2,5-dimethylthiophene (3.36 g, 30 mmol) in HOAc (50 mL)at 0° C. was added NCS (4.42 g, 33 mmol) in one portion. The reactionmixture was warmed gradually to room temperature and stirred overnight.The mixture was then treated with Na₂SO₃ and water, followed byextraction with EtOAc. The combined organic layers were washed withbrine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

6. 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene

(a) (E)-ethyl 3-(5-methylthiophen-2-yl)acrylate

To a solution of 5-methylthiophene-2-carbaldehyde (63 g, 0.5 mol) inCH₂Cl₂ (200 mL) was added triphenylphosphorane (191.4 g, 0.55 mol) atroom temperature and stirred overnight. After concentration, the crudeproduct was purified by column chromatography to give the titlecompound.

(b) (E)-3-(5-methylthiophen-2-yl)acrylic acid

To a solution of (E)-ethyl 3-(5-methylthiophen-2-yl)acrylate (80 g, 408mmol) in methanol (2000 mL) was added NaOH (130 g, 3.25 mol) and water(2000 mL) at room temperature. The mixture was heated to 50° C. andstirred for 0.5 h. After the starting material was consumed completelyas shown by TLC, the reaction mixture was concentrated. The crudeproduct was used directly without further purification.

(c) 3-(5-methylthiophen-2-yl) propanoic acid

To a solution of (E)-3-(5-methylthiophen-2-yl)acrylic acid (20 g, 119mmol) was dissolved in water (1000 mL) was added a catalytic amount ofPd/C. A vacuum was applied and the reaction mixture was back filled withhydrogen gas three times. The resulting mixture was stirred underatmospheric H₂. After the reduction was complete, the reaction mixturewas filtered and the filter cake was washed with water. The filtrate wasacidified to pH 2, extracted with EtOAc, and dried over anhydrousNa₂SO₄. The solvent was removed under reduced pressure to give the titlecompound.

(d) 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one

To a solution of 3-(5-methylthiophen-2-yl) propanoic acid (20 g, 117mmol) in DCE (200 mL) was added PPA (300 g) and the resulting mixturewas refluxed overnight. After concentration, the reaction mixture wastreated with solid NaCO₃, followed by addition of water. After stirringfor 30 minutes, the mixture was extracted with EtOAc and the organiclayer was washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound.

(e) 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophene

To a solution of 2-methyl-5,6-dihydro-4H-cyclopenta[b]thiophen-4-one (5g, 33 mmol) in ethylene glycol (10 mL) and water (2 mL) was added KOH(7.4 g, 132 mmol) and hydrazine hydrate (50 mL). The resulting mixturewas then refluxed for 48 h. After cooling to rt, the reaction wasquenched with water and extracted with EtOAc. The organic layer was thenwashed with brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

7. 2,3,4-trimethylthiophene

(a) 2-bromo-3,4-dimethylthiophene

To a solution of 3,4-dimethylthiophene (2 g, 17.8 mmol) in DCM (100 mL)was added NBS (3.2 g, 17.8 mmol) and the mixture was stirred overnightat rt. After concentration, the crude product was purified by columnchromatography to give the title compound.

(b) 2,3,4-trimethylthiophene

To a solution of 2-bromo-3,4-dimethylthiophene (1 g, 5.2 mmol) in THF(50 mL) under N₂ at −60° C. was added n-BuLi (2.1 mL, 5.2 mmol, 2.5 M inhexane) dropwise. After stirring at −78° C. for 1 h, the reactionmixture was allowed to warm to −20° C. and stirred for 0.5 h. Thereaction mixture was then cooled to −78° C. and CH₃I (1.5 g, 10 mmol)was added. The reaction mixture was then warmed gradually to rt andstirred overnight. The mixture was poured into water, extracted withethyl ether (3×100 mL), and the combined organic layers were dried overanhydrous Na₂SO₄. After concentration, the crude product was purified bycolumn chromatography to give the title compound.

8. 2,3-dimethyl-5-phenylthiophene

(a) 5-bromo-2,3-dimethylthiophene

To a solution of 2,3-dimethylthiophene (2.24 g, 2 mmol) in DCM (50 mL)was added NBS (3.56 g, 2 mmol) and the mixture was stirred overnight.After concentration, the crude product was purified by columnchromatography to give the title compound.

(b) 2,3-dimethyl-5-phenylthiophene

To a solution of 5-bromo-2,3-dimethylthiophene (1.9 g, 1 mmol) in water(10 mL) and 1,4-dioxane (25 mL) was added Pd(OAc)₂ (22.4 mg, 0.1 mmol),triphenylphosphine (118 mg, 0.45 mmol), phenylboronic acid (244 mg, 2mmol) and Na₂CO₃ (318 mg, 3 mmol). The reaction mixture was refluxed for4 h. The mixture was then poured into water and extracted with diethylether (3×20 mL). The combined organic layers were then dried overanhydrous Na₂SO₄. After filtration and concentration, the crude productwas purified by column chromatography to give the title compound.

9. 2-phenylthiophene

(a) 2-phenylthiophene

A solution of 4-bromo-2-methylthiophene (3.6 g, 20.3 mmol),phenylboronic acid (5.0 g, 40.7 mmol), Pd (OAc)₂ (456 mg, 2.03 mmol),PPh₃ (2.4 g, 9.1 mmol) and Na₂CO₃ (6.5 g, 60.9 mmol) in dioxane (10 mL)and water (10 mL) was refluxed under N₂ for 12 h. After cooling to rt,the reaction mixture was extracted with EtOAc several times. Thecombined organic layers were washed with brine and dried over anhydrousNa₂SO₄. After filtration and concentration, the crude product waspurified by column chromatography to give the title compound.

10. 2,4-dimethylthiophene

(a) 2,4-dimethylthiophene

To a solution of 4-bromo-2-methylthiophene (5 g, 28.25 mmol) andNi(dppf)Cl₂ (46 mg, 0.085 mmol) in ether (20 mL) under nitrogenatmosphere was added MeMgBr (4.2 g, 35.3 mmol) slowly and the reactionmixture was heated at reflux for 24 h. After cooling to rt, the reactionwas diluted with water and extracted with ether (50 mL×3). The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound.

11. 2-ethyl-4-methylthiophene

(a) 2-bromo-5-ethylthiophene

To a solution of 2-ethylthiophene (5 g, 44.6 mmol) in CHCl₃ and AcOH(1:1, 60 mL) at 0° C. was added NBS (8.7 g, 49.6 mmol) in and theresulting mixture was stirred for 3 h. After the starting material wasconsumed completely as shown by TLC, the reaction was quenched withsaturated sodium carbonate and extracted with CHCl₃. The combinedorganic layers were washed with brine and dried over anhydrous MgSO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound.

(b) 3-bromo-5-ethylthiophene

To a solution of 2-bromo-5-ethylthiophene (4 g, 21.05 mmol) in anhydrousTHF (50 mL) at −70° C. under nitrogen atmosphere was added LDA (42.1mmol) dropwise and the resulting mixture was stirred for 2 h. MeOH (120mL) was then added to the reaction and stirring was continued foranother 1 h. The temperature was then allowed to warm to roomtemperature and the reaction mixture was quenched with saturated sodiumcarbonate and extracted with EtOAc (200 mL×3). The combined organiclayers were washed with brine and dried over anhydrous MgSO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound.

(c) 2-ethyl-4-methylthiophene

To a solution of 4-bromo-2-ethylthiophene (5 g, 28.25 mmol) andNi(dppf)Cl₂ (46 mg, 0.085 mmol) in anhydrous ether (20 mL) undernitrogen atmosphere was added MeMgBr (4.2 g, 35.3 mmol) slowly. Thereaction solution was then heated at reflux for 24 h. After cooling toroom temperature, the reaction was diluted with water and extracted withether (20 mL×3). The combined organic layers were washed with brine anddried over anhydrous MgSO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound.

12. 2-fluorobenzo[b]thiophene

(a) 2-fluorobenzo[b]thiophene

To a solution of benzo[b]thiophene (1.34 g, 10 mmol) in anhydrous THF(100 mL) at −78° C. was added butyl lithium (4.4 mL, 11 mmol, 2.5 M inhexane) dropwise. After stirring at −78° C. for 30 minutes,N-fluorobenzenesulfonimide (NFSI, 6.3 g, 20 mmol) was added. Thereaction mixture was stirred at −78° C. for 30 minutes. The mixture waswarmed gradually to room temperate and stirred for two days followed byquenching with water and extracting with ether (3×50 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated to give a crudeproduct that was purified by column chromatography to provide the titlecompound.

13. 2-ethylbenzo[b]thiophene

(a) 2-ethylbenzo[b]thiophene

To a solution of benzo[b]thiophene (1.34 g, 10 mmol) in anhydrous THF(100 mL) at −78° C. was added butyl lithium (4.4 mL, 11 mmol, 2.5 M inhexane) dropwise. After stirring at −78° C. for 30 minutes, diethylsulfate (2.34 g, 15 mmol) was added dropwise. The reaction mixture wasthen warmed to room temperature and stirred for two days. The mixturewas quenched with water and extracted with diethyl ether. The organiclayer was dried over Na₂SO₄ and concentrated to give a crude product.The crude product was purified by column chromatography to provide thetitle compound.

14. 5-chloro-2-methylbenzo[b]thiophene

(a) (4-chlorophenyl)(2,2-dimethoxyethyl)sulfane

To a solution of 4-chlorobenzenethiol (100 mmol) and K₂CO₃ (13.8 g, 100mmol) in DMF (150 mL) at 0° C. was added 2-bromo-1,1-dimethoxyethane(18.7 g, 110 mmol). After the benzenethiol was consumed completely asshown by TLC, water (200 mL) was added and extracted with EtOAc (3×100mL). The combined organic layers were washed with brine (3×50 mL) anddried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound.

(b) 5-chlorobenzo[b]thiophene

(4-chlorophenyl)(2,2-dimethoxyethyl)sulfane (95 mmol) was dissolved inchlorobenzene (50 mL). The resulting mixture was added dropwise toboiling polyphosphoric acid (200 g) in chlorobenzene (100 mL) over 10minutes. The mixture was then poured into ice water (500 mL) and Na₂CO₃was added until the pH 8. The mixture was then extracted with EtOAc(3×100 mL), and the combined organic layers were washed with brine (3×50mL) and dried over anhydrous Na₂SO₄. After filtration and concentration,the crude product was purified by column chromatography to give thetitle compound.

(c) 2-bromo-5-chlorobenzo[b]thiophene

To a solution of 5-chlorobenzo[b]thiophene (30 mmol) in AcOH (10 mL) andDCM (50 mL) at room temperature was added NBS (30 mmol) in one portion.After stirring overnight, the reaction mixture was treated with Na₂SO₃and water, followed by extraction with EtOAc. The combined organiclayers were washed with brine and dried over anhydrous Na₂SO₄. Afterfiltration and concentration, the crude product was purified by columnchromatography to give the title compound

(d) 5-chloro-2-methylbenzo[b]thiophene

To a solution of 2-bromo-5-chlorobenzo[b]thiophene (25 mmol) in dry THF(100 mL) under nitrogen at −78° C. was added butyl lithium (10 mL, 2.5 Min hexane) dropwise. The resulting mixture was stirred at −78° C. for 30minutes. It was then warmed to −20° C. and iodomethane (7.1 g, 50 mmol)was added. After stirring at −20° C. for 30 minutes, the reactionmixture was poured into water and extracted with ether (3×50 mL). Thecombined organic layers were washed with brine (3×50 mL) and dried overanhydrous Na₂SO₄. After concentration, the crude product was purified bycolumn chromatography to give the title compound.

15. 3-chlorobenzo[b]thiophene

(a) 3-chlorobenzo[b]thiophene was synthesized according to: J. Org.Chem. 1987, 52, 169-172. 16.6-(3-chloro-5-methylthiophen-2-yl)-1,6-dihydropyrimidine-4-chloro-2-methylthiophene

(a) The title compound was synthesized according to: WO 2011/069063 17.4,5,6,7-tetrahydrobenzo[c]thiophene

(a) 4,5,6,7-tetrahydrobenzo[c]thiophene was synthesized according to: J.Org. Chem. 2006, 71, 3154-3158. 18. benzo[c]thiophene

(a) benzo[c]thiophene was synthesized according to: J. Org. Chem. 1985,50, 4969-4971 19. 5-chlorobenzo[c]thiophene

(a) 5-chlorobenzo[c]thiophene was synthesized according to: J. Org.Chem. 1985, 50, 4969-4971.

Generic Pyrimidine Synthetic Schemes

20. 1-ethylpyrimidin-1-ium bromide

(a) 1-ethylpyrimidin-1-ium bromide

In a 5 mL microwave reaction tube, bromoethane (2 mL) and pyrimidine(320 mg, 4 mmol) was added and the resulting mixture was heated at 80°C. in the microwave reactor for 20 minutes. After cooling to rt, thereaction mixture was filtered and the filter cake was washed with etherand dried under vacuum to give the crude title compound.

21. 5-chloro-2-methylpyrimidine

(a) 5-chloro-2-methylpyrimidine

To a solution of 2,5-dichloropyrimidine (5 mmol) and Ni(dppf)Cl₂ (0.25mmol) in ether (30 mL) was added MeMgBr (6 mmol, 1M in THF) dropwiseunder nitrogen atmosphere and the resulting mixture was refluxedovernight. After cooling to rt, water (20 mL) was added and the mixturewas extracted with ether (3×35 mL). The combined organic layers werewashed with brine and dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

22. 5-chloro-4-methylpyrimidine

(a) 5-chloro-4-methyl-4,5-dihydropyrimidine

To a solution of 5-chloropyrimidine (5 mmol) and Ni(dppf)Cl₂ (0.25 mmol)in ether (30 mL) was added MeMgBr (6 mmol, 1M in THF) dropwise undernitrogen atmosphere and the resulting mixture was refluxed overnight.After cooling to rt, water (20 mL) was added and the mixture wasextracted with ether (3×35 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄. After filtration andconcentration, the crude product was purified by column chromatographyto give the title compound.

(b) 5-chloro-4-methylpyrimidine

To a solution of 5-chloro-4-methyl-4,5-dihydropyrimidine (2 g) in THF(30 mL) was added DDQ (1 g) dropwise at 0° C. and the resulting mixturewas stirred for 6 hours. After the5-chloro-4-methyl-4,5-dihydropyrimidine was consumed completely as shownby TLC, water (30 mL) was added and the mixture was extracted with EtOAc(3×50 mL). The combined organic layers were washed with brine and driedover anhydrous Na₂SO₄. After filtration and concentration, the crudeproduct was purified by column chromatography to give the titlecompound.

23. 5-phenylpyrimidine

(a) 5-phenylpyrimidine

A 100 mL round-bottom flask was charged with 5-chloropyrimidine (5mmol), phenylboronic acid (1.22 g, 10 mmol), PPh₃ (265 mg, 1 mmol) andPd(OAc)₂ (224 mg, 1 mmol) in dioxide (50 mL) under nitrogen at roomtemperature. After stirring for 30 minutes, Na₂CO₃ (159 mg, 7.5 mmol)and H₂O (10 mL) were added and the resulting mixture was heated atreflux for 3 h. After cooling to rt, the reaction mixture was pouredinto water and extracted with EtOAc (3×50 mL). The combined organiclayers were washed with brine (3×50 mL) and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound.

24. 2-methoxypyrimidine

(a) 2-methoxypyrimidine

A solution of 5-chloropyrimidine (5 mmol) and MeONa (5.5 mmol) in THF(30 mL) was stirred overnight at 150° C. After cooling to rt, thesolvent was removed and water (20 mL) was added to the residue. Theresulting mixture was extracted with EtOAc (3×35 mL). The combinedorganic layers were washed with brine, and dried over anhydrous Na₂SO₄.After filtration and concentration, the crude product was purified bycolumn chromatography to give the title compound.

25. 5-chloro-N-ethylpyrimidin-2-amine

(a) 5-chloro-N-ethylpyrimidin-2-amine

To a solution of 5-chloropyrimidin-2-amine (6 mmol) in THF (30 mL) wasadded NaH (6.6 mmol) in four portions at 0° C. The resulting mixture wasstirred for 1 hour. After that, MeI (6 mmol) was added to the reactionmixture dropwise at 0° C. and stirred for another 2 hours. After the5-chloropyrimidin-2-amine was consumed completely by LC-MS, water (30mL) was added to the reaction mixture and the mixture was extracted withEtOAc (3×50 mL). The combined organic layers were washed with brine,dried over anhydrous Na₂SO₄. After filtration and concentration, thecrude product was purified by column chromatography to give the titlecompound.

26. 5,6,7,8-tetrahydroquinazoline

(a) 5,6,7,8-tetrahydroquinazoline was synthesized according to:Heterocycles 2005, 65, 2593-2603. 27. thieno[3,2-d]pyrimidine

(a) The substituted pyrimidine was synthesized according to:Heterocycles, 1994 Vol. 39, No. 2. 28. Ethylpyrrolidine-2,5-dionepyridinium bromide

(a) The substituted pyrimidinium was synthesized according to: J. Het.Chem. 2008, 45, 1371-1375; Tetrahedron Lett. 2007, 48, 1571 29.6,7-dihydro-5H-cyclopenta[d]pyrimidine

(a) The substituted pyrimidine was synthesized according to: J. Org.Chem. 1986, 51, 5100-5105; J. Org. Chem. 1982, 47, 2673-2675. 30.2-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

(a) The substituted pyrimidine was synthesized according to: J. Am.Chem. Soc. 1959, 3108-3104. 31. 5-isopropyl-2-methylpyrimidine

(a) The substituted pyrimidine was synthesized according to: WO2005/95357. 32. 7-fluoroquinazoline

(a) The substituted quinazoline was synthesized according to: WO2005/35518; WO 2006/66950; J. Am. Chem. Soc. 2006, 128, 14255.

DATA Tabular Data No. Structure Methods Data  1

1 MS (ESI+): m/z 207  2

1 ¹H NMR (400 MHz, MeOD): δ 8.11 (s, 1H), 7.85 (t, J = 6.5 Hz, 2H),7.41-7.32 (m, 2H), 6.28 (s, 1H), 6.02 (brs, 1H), 2.63 (s, 3H), 1.47 (s,3H).  3

1 MS (ESI+): m/z 229 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.93-7.85 (dd, J = 16.91 Hz, 7.49 Hz, 2H), 7.45-7.34 (m, 2H), 6.47- 6.45(d, J = 8.22 Hz, 1H), 6.13-6.12 (t, J = 2.40 Hz, 1H), 5.30-5.26 (dd, J =8.25 Hz, J = 2.88 Hz, 1H), 2.64 (s, 3H).  4

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.15 (s, 1H), 6.75 (s, 1H), 6.37 (d, J =8.0 Hz, 1H), 5.47 (dd, J = 4.0, 1.5 Hz, 1H), 5.23 (dd, J = 8.0, 4.0 Hz,1H), 3.06 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H).  5

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.06 (s, 1H), 6.78 (s, 1H), 6.30 (dt, J= 10.0, 1.5 Hz, 1H), 5.47 (dd, J = 3.5, 1.5 Hz, 1H), 5.33 (dd, J = 8.0,3.5 Hz, 1H), 3.33 (s, 3H), 2.39 (s, 3H), 2.38 (s, 3H).  6

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.53 (s, 1H), 8.19 (s, 1H), 7.85 (t, J =8.0 Hz, 2H), 7.43-7.33 (m, 2H), 6.45 (d, J = 8.0 Hz, 6.05 (brs, 1H),5.23 (dd, J = 8.0, 3.2 Hz, 1H), 2.93 (s, 3H), 2.2.64 (s, 3H).  7

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.49 (brs, 1H), 8.17 (s, 1H), 7.88 (d, J= 8.0 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 7.79-7.31 (m, 2H), 6.38 (d, J =8.0 Hz, 1H), 6.04 (brs, 1H), 5.34 (dd, J = 8.0, 3.0 Hz, 1H), 3.41 (s,3H), 2.61 (s, 3H).  8

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.11 (s, 1H), 6.67 (s, 1H), 6.21 (s,1H), 5.33 (s, 1H), 3.04 (s, 3H). 2.44 (s, 3H), 2.41 (s, 3H), 1.53 (s,3H).  9

21, 3 ¹H NMR (400 MHz, MeOD): δ 8.38, (s, 1H), 8.02 (s, 1H), 6.70 (s,1H), 6.15 (s, 1H), 5.35 (s, 1H), 3.31 (s, 3H), 2.41 (s, 3H), 2.39 (s,3H), 1.55 (s, 3H).  10

1 ¹H NMR (400 MHz, CDCl₃): δ 8.33 (s, 1H), 7.25 (dd, J = 8.0, 1.5 Hz,1H), 7.16 (s, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.52 (s, 1H), 6.18 (s, 1H),2.47 (s, 3H), 2.35 (s, 3H).  11

33, 1 ¹H NMR (400 MHz, CDCl₃): δ 8.58 (brs, 1H), 7.41 (s, 1H), 7.13 (d,J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.98 (s, 1H),2.46 (s, 3H), 2.23 (s, 3H).  12

33, 1 ¹H NMR (400 MHz, MeOD): δ 8.57 (brs, 1H), 7.38 (d, J = 8.0 Hz,1H), 7.21 (d, J = 8.0 Hz, 1H), 6.80 (s, 1H), 6.30 (s, 1H), 5.93 (s, 1H),2.47 (s, 3H), 2.23 (s, 3H).  13

1 ¹H NMR (400 MHz, MeOD): δ 8.18 (s, 1H), 6.82 (s, 1H), 6.75 (s, 1H),5.63 (s, 1H), 2.42 (s, 3H), 2.40 (s, 3H).  14

1 ¹H NMR (400 MHz, MeOD): δ 8.02 (s, 1H), 6.34 (d, J = 8.0 Hz, 1H), 6.04(s, 1H), 5.36 (s, 1H), 5.19 (dd, J = 8.0, 3.5 Hz, 1H), 2.23 (s, 3H),2.20 (s, 3H).  15

13, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.26 (s, 1H),7.89-7.85 (t, J = 6.77 Hz, 2H), 7.53-7.42 (m, 2H), 6.51-6.48 (d, J =8.37 Hz, 1H), 6.05 (s, 1H), 5.39-5.36 (dd, J = 8.00 Hz, J = 2.93 Hz,1H).  16

1 MS (ESI+): m/z 263  17

14, 1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.94-7.87 (m, 2H), 7.43-7.34 (m, 2H), 6.47- 6.44 (d, J = 8.25 Hz, 1H),6.14-6.12 (t, J = 2.37 Hz, 1H), 5.29-5.26 (dd, J = 8.22 Hz, J = 2.82 Hz,1H), 3.09-3.02 (q, 2H), 1.42- 1.37 (t, J = 7.53 Hz, 3H).  18

5, 1 MS (ESI+): m/z 291 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13-8.05 (m,2H), 7.99-7.83 (m, 2H), 7.80-7.74 (m, 1H), 7.54 (m, 4H), 7.49-7.46 (m,1H), 6.40-6.37 (d, J = 8.85 Hz, 1H), 6.08-5.98 (m, 1H), 5.37-5.34 (dd, J= 8.35 Hz, J = 5.37 Hz, 1H).  19

1 MS (ESI+): m/z 193 (MH⁺); ¹H NMR (300 MHz, DMSO-d₆): δ 11.38 (s, 1H),10.95 (s, 1H), 8.23 (s, 1H), 7.21 (s, 1H), 6.50- 6.47 (d, J = 7.95 Hz,1H), 5.80 (d, J = 3.27 Hz, 1H), 5.32-5.28 (m, 1H), 2.11 (s, 6H).  20

1 MS (ESI+): m/z 229 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s, 1H),7.90-7.88 (d, J = 7.08 Hz, 1H), 7.84-7.81 (d, J = 7.65 Hz, 1H),7.48-7.42 (m, 2H), 6.51-6.48 (d, J = 7.98 Hz, 1H), 6.13-6.12 (d, J =3.15 Hz, 1H), 5.48- 5.44 (dd, J = 8.01 Hz, J = 3.42 Hz, 1H), 2.48 (s,3H).  21

1 MS (ESI+): m/z 179 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),6.97-6.96 (d, J = 3.45 Hz, 1H), 6.75-6.74 (m, 1H), 6.46-6.43 (d, J =8.07 Hz, 1H), 5.70-5.69 (d, J = 2.70 Hz, 1H), 5.44-5.40 (dd, J = 8.04Hz, J = 3.63 Hz, 1H), 2.50 (s, 3H).  22

1 MS (ESI+): m/z 179 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),6.96-6.94 (d, J = 3.45 Hz, 1H), 6.75-6.74 (d, J = 1.17 Hz, 1H),6.45-6.43 (d, J = 8.10 Hz, 1H), 5.70- 5.69 (d, J = 3.54 Hz, 1H),5.44-5.40 (dd, J = 8.10 Hz, J = 0.78 Hz, 1H), 2.50 (s, 3H).  23

1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.06 (s, 1H), 6.82(s, 1H), 6.37- 6.34 (d, J = 8.19 Hz, 1H), 5.56-5.54 (dd, J = 3.24 Hz, J= 1.41 Hz, 1H), 5.25- 5.22 (dd, J = 8.16 Hz, J = 3.33 Hz, 1H), 2.87-2.76(m, 4H), 1.31-1.25 (m, 6H).  24

1 MS (ESI+): m/z 206 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),6.34-6.31 (d, J = 8.31 Hz, 1H), 5.74-5.72 (t, J = 2.37 Hz, 1H),5.17-5.13 (dd, J = 8.28 Hz, J = 2.88 Hz, 1H), 2.41 (s, 3H), 2.29 (s,3H), 2.18 (s, 3H).  25

1 MS (ESI+): m/z 192 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 9.40 (s, 1H),8.94-8.91 (dd, J = 6.54 Hz, 0.9 Hz, 1H), 8.18-8.16 (d, J = 6.54 Hz, 1H),7.41 (s, 1H), 2.87 (s, 3H), 2.49 (s, 3H).  26

7, 1 MS (ESI+): m/z 219 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),6.35-6.32 (d, J = 8.22 Hz, 1H), 5.64-5.63 (q, 1H), 5.18-5.14 (dd, J =7.47 Hz, 2.49 Hz, 1H), 2.86-2.71 (m, 4H), 2.52-2.47 (m, 2H), 2.43 (s,3H).  27

7, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.07 (s, 1H),6.33-6.30 (d, J = 8.16 Hz, 1H), 5.70-5.68 (t, J = 2.34 Hz, 1H),5.16-5.13 (dd, J = 7.68 Hz, 2.31 Hz, 1H), 2.75-2.55 (m, 4H), 2.42 (s,3H), 1.84-1.83 (m, 4H).  28

8, 1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.05 (s, 1H),6.42-6.40 (d, J = 8.16 Hz, 1H), 5.83-5.81 (dd, J = 3.60 Hz, 1.50 Hz,1H), 5.36-5.32 (m, 1H), 2.35 (s, 3H), 2.14 (s, 3H), 2.00 (s, 3H).  29

9, 1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.96 (s, 1H),7.49-7.36 (m, 5H), 6.26-6.24 (d, J = 8.19 Hz, 1H), 5.71-5.69 (t, J =2.40 Hz, 1H), 5.24-5.21 (dd, J = 8.24 Hz, J = 2.78 Hz, 1H), 2.41 (s,3H), 2.32 (s, 3H).  30

9, 1 MS (ESI+): m/z 303 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),7.59-7.53 (dd, J = 8.01 Hz, J = 1.26 Hz, 2H), 7.44-7.39 (d, J = 7.44 Hz,2H), 7.28-7.23 (t, J = 7.77 Hz, 1H), 5.22 (s, 1H), 5.02-5.00 (d, J =6.90 Hz, 1H), 2.39 (s, 3H), 2.27 (s, 3H).  31

9, 1 MS (ESI+): m/z 303 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.19-8.16 (m,1H), 7.97 (s, 1H), 7.79 (m, 1H), 7.46-7.35 (m, 2H), 6.27-6.24 (d, J =8.04 Hz, 1H), 5.69 (s, 1H), 5.25-5.22 (m, 1H), 2.31 (s, 3H), 2.25 (s,3H).  32

9, 1 MS (ESI+): m/z 303 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.98 (s, 1H),7.48-7.42 (m, 2H), 7.38-7.35 (m, 2H), 6.27- 6.24 (d, J = 8.31 Hz, 1H),5.69-5.68 (t, J = 2.37 Hz, 1H), 5.24-5.21 (dd, J = 8.22 Hz, 2.10 Hz,1H), 2.41 (s, 3H), 2.31 (s, 3H).  33

9, 1 MS (ESI+): m/z 227  34

15, 1 MS (ESI+): m/z 263 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.26 (s, 1H),7.90 (s, 1H), 7.87- 7.84 (d, J = 8.58 Hz, 1H), 7.38-7.34 (dd, J = 8.58Hz, J = 1.92 Hz, 1H), 6.51- 6.48 (d, J = 7.83 Hz, 1H), 6.13-6.11 (t, J =2.37 Hz, 1H), 5.30-5.27 (dd, J = 8.18 Hz, J = 2.48 Hz, 1H), 2.66 (s,3H).  35

1 MS (ESI+): m/z 179 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.32 (s, 1H),6.78-6.77 (d, J = 3.36 Hz, 1H), 6.63-6.62 (m, 1H), 6.25-6.23 (d, J =7.71 Hz, 1H), 5.40-5.36 (d, J = 3.42 Hz, 1H), 4.96-4.93 (m, 1H), 2.47(s, 3H).  36

1 MS (ESI+): m/z 193 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.51-7.25 (m,1H), 6.87-6.81 (m, 1H), 6.64-6.62 (m, 1H), 6.26-6.23 (m, 1H), 5.43- 5.36(m, 1H), 4.96-4.93 (m, 1H), 2.84-2.76 (m, 2H), 1.30-1.26-2.76 (m, 3H). 37

10, 1 MS (ESI+): m/z 241 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.14 (s, 1H),7.66-7.65 (m, 2H), 7.63-7.33 (m, 4H), 7.18- 7.17 (d, J = 3.9 Hz, 1H),6.51-6.49 (d, J = 8.10 Hz, 1H), 5.80-5.78 (m, 1H), 5.52-5.48 (m, 1H). 38

10, 1 MS (ESI+): m/z 259 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.14 (s, 1H),7.69-7.64 (m, 2H), 7.33-7.31 (d, J = 3.72 Hz, 1H), 7.19-7.14 (m, 3H),6.52-6.49 (d, J = 8.10 Hz, 1H), 5.80-5.78 (m, 1H), 5.52-5.48 (m, 1H). 39

11, 1 MS (ESI+): m/z 194 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.08 (s, 1H),6.59 (s, 1H), 6.44- 6.41 (d, J = 8.10 Hz, 1H), 5.79-5.78 (m, 1H), 5.37-5.33 (m, 1H), 2.43 (s, 3H), 2.21 (s, 3H).  40

12, 1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.07 (s, 1H),6.63 (s, 1H), 6.43- 6.41 (d, J = 8.16 Hz, 1H), 5.80-5.78 (m, 1H), 5.38-5.34 (m, 1H), 2.84-2.77 (m, 2H), 2.22 (s, 3H), 1.30-1.22 (m, 3H).  41

9, 1 MS (ESI+): m/z 255 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13 (s, 1H),7.67-7.61 (d, J = 7.14 Hz, 2H), 7.45-7.34 (m, 3H), 7.23 (s, 1H), 6.50-6.47 (d, J = 8.19 Hz, 1H) 5.89-5.88 (d, J = 2.22 Hz, 1H), 5.46-5.42 (m,1H), 2.32 (s, 3H).  42

9, 1 MS (ESI+): m/z 273 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.63-7.58 (m,2H), 7.46 (s, 1H), 7.19-7.08 (m, 3H), 6.33- 6.30 (d, J = 7.83 Hz, 1H),5.62.-5.61 (d, J = 3.15 Hz, 1H), 5.08-5.02 (m, 1H), 2.27 (s, 3H).  43

11, 1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.10 (s, 1H),6.55 (s, 1H), 6.24- 6.22 (d, J = 7.47 Hz, 1H), 5.47-5.46 (m, 1H), 5.84.-4.80 (m, 1H), 2.61-2.53 (m, 2H), 2.44 (s, 3H), 1.22-1.17 (t, J = 7.56Hz, 3H).  44

12, 5, 1 MS (ESI+): m/z 255 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.06 (s,1H), 7.50-7.36 (m, 5H), 6.80 (s, 1H), 6.40-6.37 (d, J = 8.13 Hz, 1H),5.77.- 5.75 (m, 1H), 5.43-5.39 (m, 1H), 2.54 (s, 3H).  45

12, 5, 1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.45-7.32(m, 5H), 7.20-7.16 (s, 1H), 6.74 (s, 1H), 6.24-6.17 (m, 1H), 5.52.-5.50(m, 1H), 4.84-4.80 (m, 1H), 2.92- 2.81 (m, 2H), 1.36-1.31 (t, J = 7.52Hz, 3H).  46

12, 5, 1 MS (ESI+): m/z 273 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.52-7.41(m, 2H), 7.24-7.04 (m, 3H), 6.88 (s, 1H), 6.19- 6.16 (d, J = 7.71 Hz,1H), 5.43.-5.42 (m, 1H), 4.78- 4.74 (m, 1H), 2.49 (s, 3H).  47

1, chiral purification (ESI+): m/z 193 (MH⁺); ¹H NMR (400 MHz, CDCl₃): δ8.33 (s, 1H), 6.63 (s, 1H), 6.19 (d, J = 8.1 Hz, 1H), 5.34 (dd, J = 3.3,1.1 Hz, 1H), 5.04 (dd, J = 8.1, 3.3 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 3H) 48

1, chiral purification (ESI+): m/z 193 (MH⁺); ¹H NMR (400 MHz, CDCl₃): δ8.33 (s, 1H), 6.63 (s, 1H), 6.19 (d, J = 8.1 Hz, 1H), 5.34 (dd, J = 3.3,1.1 Hz, 1H), 5.04 (dd, J = 8.1, 3.3 Hz, 1H), 2.37 (s, 3H), 2.33 (s, 3H) 49

3 MS (ESI+): m/z 207  50

11, 3 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s, 1H),6.61-6.59 (m, 1H), 6.45-6.38 (m, 1H), 5.75- 5.73 (m, 1H), 5.37-5.33 (m,1H), 3.15 (s, 3H), 2.45 (s, 3H), 2.24 (s, 3H).  51

1 MS (ESI+): m/z 257 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.29 (s, 1H),7.38-7.33 (m, 1H), 7.25-7.20 (td, J = 7.61 Hz, 1.05 Hz, 1H), 7.11-7.08(d, J = 7.89 Hz, 1H), 6.83- 6.81 (d, J = 7.71 Hz, 1H), 6.38 (s, 1H),2.41 (s, 3H), 2.27 (s, 3H), 1.93 (s, 3H).  52

1 MS (ESI+): m/z 271 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.26 (s, 1H),7.39-7.34 (t, J = 7.68 Hz, 1H), 7.27-7.22 (m, 1H), 7.15-7.13 (d, J =7.89 Hz, 1H), 6.94-6.91 (d, J = 7.71 Hz, 1H), 6.55 (s, 1H), 6.21 (s,1H), 2.98-2.89 (m, 2H), 2.78-2.70 (q, 2H), 1.36 (t, J = 7.53 Hz, 3H),1.24-1.19 (t, J = 7.53 Hz, 3H).  53

9, 1 MS (ESI+): m/z 353 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13 (s, 1H),7.50-7.39 (m, 3H), 7.32-7.18 (m, 3H), 6.92- 6.90 (m, 2H), 6.04 (s, 1H),2.91 (s, 3H), 2.10 (s, 3H).  54

9, 1 MS (ESI+): m/z 319 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s, 1H),7.42-7.25 (m, 6H), 7.24-7.20 (td, J = 7.60 Hz, 1.07 Hz, 1H), 7.03-7.00(d, J = 7.84 Hz, 1H), 6.85- 6.83 (d, J = 7.74 Hz, 1H), 6.28 (s, 1H),2.38 (s, 3H), 2.00 (s, 3H).  55

7, 1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.29 (s, 1H),7.39-7.33 (t, J = 7.41 Hz, 1H), 7.27-7.22 (t, J = 7.74 Hz, 1H),7.13-7.10 (d, J = 7.92 Hz, 1H), 6.93- 6.90 (d, J = 7.65 Hz, 1H), 6.29(s, 1H), 2.82-2.71 (m, 2H), 2.56 (s, 3H), 2.47- 2.23 (m, 3H), 2.07-1.97(m, 1H).  56

15, 1 MS (ESI+): m/z 313 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.41 (s, 1H),7.49-7.46 (m, 1H), 7.41-7.35 (m, 2H), 7.32- 7.27 (m, 1H), 7.21-7.17 (m,2H), 6.86-6.84 (d, J = 8.07 Hz, 1H), 6.74 (s, 1H), 2.71 (s, 3H).  57

15, 1 MS (ESI+): m/z 313 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.43 (s, 1H),7.86-7.83 (d, J = 8.58 Hz, 1H), 7.50 (brs, 1H), 7.43-7.38 (t, J = 8.13Hz, 1H), 7.33-7.29 (dd, J = 8.58 Hz, 1.92 Hz, 1H), 7.24-7.18 (m, 2H),6.87- 6.84 (d, J = 7.68 Hz, 1H), 6.74 (s, 1H), 2.67 (s, 3H).  58

13, 1 MS (ESI+): m/z 283 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.45 (s, 1H),7.89-7.83 (m, 1H), 7.63-7.59 (m 1H), 7.43- 7.39 (m, 3H), 7.26-7.21 (m,2H), 7.03-7.01 (d, J = 7.74 Hz, 1H), 6.73 (s, 1H).  59

14, 1 MS (ESI+): m/z 293 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.38 (s, 1H),7.88-7.86 (m, 1H), 7.55-7.44 (brs, 1H), 7.40- 7.33 (m, 1H), 7.31-7.26(m, 2H), 7.21-7.15 (m, 2H), 6.84-6.81 (d, J = 7.71 Hz, 1H), 6.74 (s,1H), 3.12-3.09 (m, 2H), 1.45- 1.40 (t, J = 7.34 Hz, 3H).  60

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.30 (s, 1H),7.42-7.38 (m, 1H), 7.30-7.25 (m, 1H), 7.17- 7.15 (d, J = 7.92 Hz, 1H),7.07-7.03 (m, 2H), 6.53 (s, 1H), 2.76 (s, 3H), 2.19 (s, 3H).  61

11, 1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.29 (s, 1H),7.42-7.37 (m, 1H), 7.30-7.25 (m, 1H), 7.17- 7.14 (d, J = 7.92 Hz, 1H),7.07-7.04 (d, J = 7.65 Hz, 1H), 6.59 (s, 1H), 6.46 (s, 1H), 2.39 (s,3H), 2.28 (s, 3H)  62

11, 1 MS (ESI+): m/z 257 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.28 (s, 1H),7.42-7.37 (m, 1H), 7.30-7.25 (m, 1H), 7.16- 7.13 (d, J = 7.92 Hz, 1H),7.05-7.02 (d, J = 7.71 Hz, 1H), 6.71 (s, 1H), 6.47 (s, 1H), 2.74-2.62(m, 2H), 2.41 (s, 3H), 1.27-1.22 (t, J = 7.56 Hz, 3H).  63

12, 1 MS (ESI+): m/z 305 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.23 (s, 1H),7.50-7.34 (m, 6H), 7.27-7.21 (m, 1H), 7.10- 7.07 (d, J = 7.92 Hz, 1H),6.96-6.94 (d, J = 7.56 Hz, 1H), 6.79 (s, 1H), 6.40 (s, 1H), 2.49 (s,3H).  64

1 MS (ESI+): m/z 279 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.39 (s, 1H),7.86-7.80 (m, 2H), 7.48-7.37 (m, 3H), 7.31- 7.26 (m, 1H), 7.22-7.19 (d,J = 7.92 Hz, 1H), 7.11- 7.09 (d, J = 7.68 Hz, 1H), 6.79 (s, 1H), 2.61(s, 3H).  65

9, 1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 7.33 (m, 3H),7.18-7.13 (m, 3H), 7.06-6.93 (m, 3H), 6.84- 6.82 (m, 1H), 6.75-6.73 (m,1H), 6.13-6.08 (m, 1H), 2.14 (s, 3H).  66

1, chiral purification MS (ESI+): m/z 229 (MH⁺); ¹H NMR (300 MHz, MeOD):δ 8.21 (s, 1H), 7.93-7.85 (dd, J = 16.91 Hz, 7.49 Hz, 2H), 7.45-7.34 (m,2H), 6.47- 6.45 (d, J = 8.22 Hz, 1H), 6.13-6.12 (t, J = 2.40 Hz, 1H),5.30-5.26 (dd, J = 8.25 Hz, J = 2.88 Hz, 1H), 2.64 (s, 3H).  67

1, chiral purification MS (ESI+): m/z 229 (MH⁺); ¹H NMR (300 MHz, MeOD):δ 8.21 (s, 1H), 7.93-7.85 (dd, J = 16.91 Hz, 7.49 Hz, 2H), 7.45-7.34 (m,2H), 6.47- 6.45 (d, J = 8.22 Hz, 1H), 6.13-6.12 (t, J = 2.40 Hz, 1H),5.30-5.26 (dd, J = 8.25 Hz, J = 2.88 Hz, 1H), 2.64 (s, 3H).  68

15, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.24 (s, 1H),7.88-7.84 (dd, J = 9.10 Hz, 5.10 Hz, 1H), 7.62-7.58 (dd, J = 10.50 Hz,2.40 Hz, 1H), 7.20- 7.14 (td, J = 8.82 Hz, 2.32 Hz, 1H), 6.50-6.47 (d, J= 8.13 Hz, 1H), 6.11-6.10 (m, 1H), 5.30-5.26 (dd, J = 8.19 Hz, 2.64 Hz,1H), 2.65 (s, 3H).  69

15, 1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.74-7.68 (m, 2H), 7.23-7.20 (d, J = 6.49 Hz, 1H), 6.47-6.45 (d, J =7.35 Hz, 1H), 6.11-6.09 (m, 1H), 5.29-5.25 (dd, J = 8.37 Hz, 2.37 Hz,1H), 2.63 (s, 3H), 2.48 (s, 3H).  70

15, 1 MS (ESI+): m/z 259 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),7.74 (s, 1H), 7.37- 7.36 (m, 1H), 7.04-7.02 (m, 1H), 6.46-6.44 (d, J =8.13 Hz, 1H), 5.83-5.81 (dd, J = 3.65 Hz, 1.10 Hz, 1H), 5.38-5.34 (dd, J= 8.12 Hz, 3.68 Hz, 1H), 4.00 (s, 3H), 2.59 (s, 3H).  71

15, 1 MS (ESI+): m/z 263.5 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.22 (s,1H), 7.92-7.86 (m, 2H), 7.44-7.40 (m, 1H), 6.48- 6.45 (d, J = 8.46 Hz,1H), 6.11 (m, 1H), 5.28-5.26 (m, 1H), 2.64 (s, 3H).  72

15, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.93-7.88 (m, 1H), 7.66-7.62 (dd, J = 8.76 Hz, 2.43 Hz, 1H), 7.25-7.19(td, J = 8.97 Hz, 2.46 Hz, 1H), 6.48-6.45 (dd, J = 8.15 Hz, 0.60 Hz,1H), 6.12-6.10 (m, 1H), 5.29- 5.26 (m, 1H), 2.63 (s, 3H).  73

15, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.14 (s, 1H),7.69-7.66 (d, J = 8.22 Hz, 1H), 7.39-7.32 (m, 1H), 7.18-7.11 (dd, J =12.60 Hz, 7.86 Hz, 1H), 6.38-6.35 (dd, J = 8.25 Hz, 1.80 Hz, 1H),6.31-6.30 (m, 1H), 5.28-5.25 (dd J = 8.40 Hz, J = 1.80 Hz, 1H), 2.65 (s,3H).  74

15, 1 MS (ESI+): m/z 263 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.23 (s, 1H),7.90-7.87 (dd, J = 7.35 Hz, 1.38 Hz, 1H), 7.48-7.40 (m, 2H), 6.49- 6.46(d, J = 8.04 Hz, 1H), 5.31-5.27 (dd, J = 8.12 Hz, J = 2.36 Hz, 1H), 2.65(s, 3H).  75

6, 1 MS (ESI+): m/z 226 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),6.37-6.34 (d, J = 8.43 Hz, 1H), 5.82-5.80 (m, 1H), 5.17-5.13 (dd, J =7.53 Hz, J = 2.31 Hz, 1H), 2.46 (s, 3H), 2.36 (s, 3H).  76

16, 1 MS (ESI+): m/z 293 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.25 (s, 1H),8.00-7.97 (m, 1H), 7.91-7.88 (m, 1H), 7.60- 7.50 (m, 2H), 6.56 (d, J =8.13 Hz, 1H), 6.18-6.17 (m, 1H), 5.52-5.48 (dd, J = 3.06 Hz, J = 7.59Hz, 1H),  77

12, 1 MS (ESI+): m/z 257 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.14 (s, 1H),6.81 (s, 1H), 6.49- 6.46 (d, J = 8.04 Hz, 1H), 5.85-5.83 (dd, J = 3.60Hz, J = 1.38 Hz, 1H), 5.40- 5.36 (m, 1H), 2.51 (s, 3H).  78

1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.03 (s, 1H), 6.71(s, 1H), 6.21 (s, 1H), 5.42 (s, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 1.55(s, 3H).  79

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.62 (s, 1H), 6.56(s, 1H), 5.31 (s, 1H), 2.42 (s, 3H), 2.40 (s, 3H).  80

1 MS (ESI+): m/z 228 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.22 (s, 1H),6.77-6.75 (d, J = 5.16 Hz, 2H), 5.66 (s, 1H), 2.44 (s, 3H), 2.42 (s,3H).  81

1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.82-7.73 (m, 3H),7.68-7.63 (m, 2H), 6.81 (s, 1H), 6.53- 6.50 (dd, J = 8.01 Hz, J = 1.29Hz, 1H), 5.66-5.64 (dd, J = 3.69 Hz, J = 1.31 Hz, 1H), 5.39-5.35 (dd, J= 8.10 Hz, 3.9 Hz, 1H), 2.45 (s, 3H), 2.41 (s, 3H).  82

1 MS (ESI+): m/z 222 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.58 (s, 1H), 6.07(s, 1H), 5.10 (s, 1H), 2.40 (s, 3H), 2.38 (s, 3H), 1.53 (s, 3H).  83

1 MS (ESI+): m/z 193 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13 (s, 1H), 6.85(s, 1H), 6.49- 6.46 (d, J = 8.13 Hz, 1H), 5.86-5.85 (dd, J = 3.63 Hz, J= 1.41 Hz, 1H), 5.41- 5.37 (m, 1H), 2.91-2.83 (m, 2H), 1.33-1.28 (t, J =7.53 Hz, 3H).  84

16, 1 MS (ESI+): m/z 329 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.36 (s, 1H),7.91-8.01 (m, 2H), 7.62-7.56 (m, 2H), 6.93 (s, 1H), 6.32 (s, 1H).  85

16, 1 MS (ESI+): m/z 343 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.44 (s, 1H),7.90-7.93 (td, J = 8.64 Hz, J = 1.02 Hz, 2H), 7.43-7.60 (m, 3H), 7.28-7.34 (td, 7.61 Hz, 1H), 7.16-7.24 (m, 2H), 6.85 (s, 1H).  86

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13 (s, 1H),7.81-7.89 (m, 2H), 7.39-7.49 (m, 2H), 6.33 (s, 1H), 6.01 (s, 1H), 2.52(s, 3H), 1.67 (s, 3H).  87

1 MS (ESI+): m/z 263 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.31 (s, 1H),7.83-7.91 (m, 2H), 7.42-7.50 (m, 2H), 6.87 (s, 1H), 6.27 (s, 1H), 2.53(s, 3H).  88

1 MS (ESI+): m/z 279 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.37 (s, 1H),7.80-7.86 (m, 2H), 7.37-7.48 (m, 3H), 7.26- 7.31 (t, J = 7.49 Hz, 1H),7.19-7.21 (d, J = 7.89 Hz, 1H), 7.09-7.12 (d, J = 7.71 Hz, 1H), 6.79 (s,1H), 2.60 (s, 3H).  89

1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.75 (s, 1H),6.32-6.35 (dd, J = 8.09, J = 1.34, 1H), 5.48- 5.50 (m, 1H), 5.17-5.21(dd, J = 8.09 Hz, J = 3.38 Hz, 1H), 2.40 (s, 6H), 2.24 (s, 3H).  90

26, 1 MS (ESI+): m/z 270 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.63 (s, 1H),6.52 (s, 1H), 5.31 (s, 1H), 3.10 (s, 6H), 2.43 (s, 3H), 2.39 (s, 3H). 91

24, 1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.15 (s, 1H),7.31-7.34 (m, 5H), 6.82 (s, 1H), 6.74 (s, 1H), 5.99 (s, 1H), 2.44 (s,3H), 2.34 (s, 3H).  92

12, 1 MS (ESI+): m/z 277 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.35 (s, 1H),7.42-7.47 (t, J = 7.62 Hz, 1H), 7.18-7.22 (m, 2H), 6.39 (s, 1H),2.76-2.84 (q, 2H), 1.20-1.25 (t, J = 7.53 Hz, 3H).  93

25, 1 MS (ESI+): m/z 271 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.75 (s, 1H),6.59 (s, 1H), 5.56 (s, 1H), 4.35-4.57 (m, 2H), 2.43 (s, 3H), 2.41 (s,3H), 1.43-1.47 (t, J = 6.38 Hz, 3H).  94

25, 1 MS (ESI+): m/z 223 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.74 (s, 1H),6.28-6.31 (d, J = 7.8 Hz, 1H), 5.53-5.54 (m, 1H), 5.14-5.22 (m, 1H),4.10 (s, 3H), 2.40 (s, 6H).  95

25, 1 MS (ESI+): m/z 257 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.76 (s, 1H),6.60 (s, 1H), 5.58 (s, 1H), 4.12 (s, 3H), 2.43 (s, 3H), 2.41 (s, 3H). 96

1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.73 (s, 1H),6.33-6.36 (d, J = 8.07 Hz, 1H), 5.48-5.50 (m, 1H), 5.18-5.22 (dd, J =8.06 Hz, J = 3.38 Hz, 1H), 2.40 (s, 6H), 1.26-1.31 (t, J = 7.64 Hz, 3H). 97

25, 1 MS (ESI+): m/z 271 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.75 (s, 1H),6.59 (s, 1H), 6.57 (s, 1H), 4.35-4.55 (m, 2H), 2.43 (s, 3H), 2.41 (s,3H), 1.43-1.47 (t, J = 6.38 Hz, 3H).  98

17, 1 MS (ESI+): m/z 213 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.11 (s, 1H),7.11 (s, 1H), 6.47- 6.50 (d, J = 8.04 Hz, 1H), 5.68-5.69 (m, 1H), 5.40-5.44 (m, 1H), 2.42 (s, 3H),  99

16, 1 MS (ESI+): m/z 283 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.44 (s, 1H),7.84-7.87 (m, 2H), 7.60-7.63 (m, 1H), 7.39- 7.43 (m, 3H), 7.20-7.26 (m,2H), 7.01-7.04 (d, J = 7.62 Hz, 1H), 6.73 (s, 1H). 100

17, 1 MS (ESI+): m/z 227 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),7.02 (s, 1H), 6.48- 6.51 (d, J = 8.04 Hz, 1H), 5.70-5.71 (d, J = 3.0 Hz,1H), 5.41-5.45 (m, 1H), 2.81-2.88 (q, 2H), 1.30-1.25 (t, J = 7.52 Hz,3H). 101

17, 1 MS (ESI+): m/z 307 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s, 1H),6.52-6.54 (d, J = 8.10 Hz, 1H), 5.91-5.95 (dd, J = 8.10 Hz, 3.60 Hz,1H), 5.38-5.42 (m, 1H), 2.83- 2.96 (m, 2H), 1.27-1.32 (t, J = 7.51 Hz,3H). 102

22, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.71 (s, 1H),6.32-6.35 (d, J = 8.10 Hz, 1H), 5.48-5.49 (m, 1H), 5.20-5.24 (dd, J =8.10 Hz, 3.3 Hz, 1H), 2.71-2.81 (m, 1H), 2.41 (s, 6H), 1.32 (s, 3H),1.30 (s, 3H). 103

1 MS (ESI+): m/z 226 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.65 (s, 1H),6.43-6.45 (d, J = 6.21 Hz, 1H), 5.50-5.51 (d, J = 2.64 Hz, 1H), 2.41 (s,3H), 2.40 (s, 3H). 104

1 MS (ESI+): m/z 213 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H), 7.01(s, 1H), 6.47- 6.50 (d, J = 8.10 Hz, 1H), 5.69-5.70 (d, J = 2.79 Hz,1H), 5.40-5.44 (dd, J = 8.06 Hz, J = 3.67 Hz, 1H), 2.42 (s, 3H). 105

1 MS (ESI+): m/z 223 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.97 (s, 1H), 6.64(s, 1H), 6.04 (s, 1H), 5.50 (s, 1H), 3.63 (s, 3H), 2.40 (s, 3H), 2.39(s, 3H). 106

16, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.25 (s, 1H),7.89-7.99 (m, 2H), 7.51-7.59 (m, 2H), 6.54- 6.57 (d, J = 8.07 Hz, 1H),6.16-6.18 (dd, J = 3.56 Hz, J = 1.31 Hz, 1H), 5.47- 5.51 (dd, J = 7.53Hz, J = 3.60 Hz, 1H). 107

17, 1 MS (ESI+): m/z 357 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.38 (s, 1H),7.42-7.47 (t, J = 7.65 Hz, 1H), 7.30-7.35 (t, J = 7.58 Hz, 1H),7.13-7.21 (m, 2H), 6.61-6.63 (d, J = 6.03 Hz, 1H), 2.82-2.93 (m, 2H),1.20-1.28 (t, J = 7.53 Hz, 3H). 108

17, 1 MS (ESI+): m/z 307 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.19 (s, 1H),7.89-7.99 (m, 2H), 7.53-7.58 (m, 2H), 6.37 (m, 1H), 6.09 (m, 1H), 1.69(s, 3H). 109

26, 1 MS (ESI+): m/z 270 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.62 (s, 1H),6.53 (s, 1H), 5.30 (s, 1H), 3.23-3.30 (q, 2H), 2.24 (s, 3H), 2.39 (s,3H), 1.21-1.25 (t, J = 7.22 Hz, 3H). 110

22, 1 MS (ESI+): m/z 303 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.73-7.80 (m,3H), 6.63-6.68 (m, 2H), 6.85 (s, 1H), 6.82 (s, 1H), 5.75 (s, 1H), 2.49(s, 3H), 2.42 (s, 3H). 111

22, 1 MS (ESI+): m/z 337 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.70-7.76 (m,4H), 6.83-6.86 (m, 2H), 5.76 (s, 1H), 2.48 (s, 3H), 2.42 (s, 3H). 112

22, 1 MS (ESI+): m/z 337 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.67-7.74 (m,3H), 7.55-7.62 (m, 1H), 7.12 (s, 1H), 6.91 (s, 1H), 5.82 (s, 1H), 2.41(s, 3H), 2.40 (s, 3H). 113

16, 1 MS (ESI+): m/z 293 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.38 (s, 1H),7.86-7.88 (m, 1H), 7.46-7.55 (m, 1H), 7.18- 7.40 (m, 5H), 6.81-6.84 (d,J = 7.74 Hz, 7H), 6.74 (s, 1H), 3.09-3.12 (m, 2H), 1.38-1.45 (m, 3H).114

16, 1 MS (ESI+): m/z 277 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.33 (s, 1H),7.89-7.92 (d, J = 7.32 Hz, 1H), 7.80-7.83 (d, J = 7.59 Hz, 1H),7.36-7.47 (m, 2H), 6.87 (s, 1H), 6.28 (s, 1H), 3.04-3.12 (q, 2H),1.40-1.46 (t, J = 7.53 Hz, 3H). 115

16, 1 MS (ESI+): m/z 257 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.15 (s, 1H),7.87-7.90 (d, J = 7.26 Hz, 2H), 7.36-7.42 (m, 2H), 6.31 (s, 1H), 6.06(s, 1H), 3.04-3.17 (q, 2H), 1.49 (s, 3H), 1.39-1.44 (t, J = 7.41 Hz,3H). 116

24, 23, 1 MS (ESI+): m/z 297 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.22 (s,1H), 7.30 (m, 3H), 7.01- 7.02 (m, 2H), 6.81 (s, 1H), 5.55 (s, 1H), 2.40(s, 3H), 2.10-2.17 (q, 2H), 1.96 (s, 3H), 1.08-1.13 (t, J = 7.40 Hz,3H). 117

23, 1 MS (ESI+): m/z 277 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.32 (s, 1H),7.81-7.89 (m, 2H), 7.43-7.47 (m, 2H), 6.20 (s, 1H), 2.52 (s, 3H), 2.14(s, 3H), 118

22, 1 MS (ESI+): m/z 241 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.76 (s, 1H),6.70 (s, 1H), 5.60 (s, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 2.28 (s, 3H).119

22, 16, 1 MS (ESI+): m/z 277 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.82-7.91(m, 2H), 7.42-7.50 (m, 2H), 6.74 (s, 1H), 6.21 (s, 1H), 2.52 (s, 3H),2.33 (s, 3H). 120

22, 16, 1 MS (ESI+): m/z 291 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.89-7.92(d, J = 7.17 Hz, 1H), 7.77- 7.80 (d, J = 7.71 Hz, 1H), 7.36-7.46 (m,2H), 6.84 (s, 1H), 6.21 (s, 1H), 3.03- 3.11 (q, 2H), 2.31 (s, 3H),1.41-1.46 (t, J = 7.56, 3H). 121

26, 1 MS (ESI+): m/z 256 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.62 (s, 1H),6.53 (s, 1H), 4.84 (s, 1H), 2.88 (s, 3H), 2.42 (s, 3H), 2.39 (s, 3H).122

22, 16, 1 MS (ESI+): m/z 343 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.90-8.0(m, 2H), 7.55-7.59 (m, 2H), 6.89 (s, 1H), 6.26 (s, 1H), 2.34 (s, 3H).123

22, 16, 1 MS (ESI+): m/z 255 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.73 (s,1H), 6.71 (s, 1H), 5.60 (s, 1H), 2.53-2.55 (q, 2H), 2.44 (s, 3H), 2.42(s, 3H), 1.27-1.32 (t, J = 7.67, 3H). 124

23, 1 MS (ESI+): m/z 255 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),6.70 (s, 1H), 5.59 (s, 1H), 2.36-2.50 (m, 8H), 1.18-1.21 (t, J = 7.56,3H). 125

24, 22, 1 MS (ESI+): m/z 283 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.28-7.33(m, 5H), 6.81 (s, 1H), 6.71 (s, 1H), 5.95 (s, 1H), 2.45 (s, 3H), 2.33(s, 3H), 2.32 (s, 3H). 126

32, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.67 (s, 1H),6.17 (s, 1H), 5.38 (s, 1H), 2.46-2.54 (q, 2H), 2.43 (s, 3H), 2.40 (s,3H), 1.54 (s, 3H), 1.25-1.30 (t, J = 7.67 Hz, 3H). 127

32, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.68 (s, 1H),6.16 (s, 1H), 5.37 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H), 2.23 (s, 3H),1.53 (s, 3H), 128

24, 22, 1 MS (ESI+): m/z 381 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.69-7.70(m, 1H), 7.55-7.60 (m, 3H), 7.31-7.39 (m, 1H), 7.15-7.24 (m, 2H), 7.02-7.08 (m, 2H), 6.80 (s, 1H), 6.09 (s, 1H), 2.51 (s, 3H), 2.37 (s, 3H).129

22, 1 MS (ESI+): m/z 321 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.66-7.72 (m,1H), 7.54-7.60 (m, 3H), 6.85-6.86 (m, 2H), 5.77 (s, 1H), 2.49 (s, 3H),2.43 (s, 3H). 130

23, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.81 (s, 1H),6.71 (s, 1H), 5.58 (s, 1H), 2.43 (s, 3H), 2.41 (s, 3H), 2.09 (s, 3H).131

24, 22, 1 MS (ESI+): m/z 381 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.70-7.84(m, 2H), 7.29-7.50 (m, 4H), 7.11-7.18 (m, 2H), 6.84-6.85 (m, 2H), 6.13(s, 1H), 2.36 (s, 6H). 132

22, 1 MS (ESI+): m/z 321 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.76-7.82 (m,1H), 7.68-7.73 (t, J = 7.34 Hz, 1H), 7.39-7.49 (m, 2H), 6.88 (s, 1H),6.85 (s, 1H), 5.80 (s, 1H), 2.48 (s, 3H), 2.44 (s, 3H). 133

22, 1 MS (ESI+): m/z 337 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.80-7.83 (m,2H), 7.64-7.67 (m, 2H), 6.84 (s, 2H), 5.76 (s, 1H), 2.48 (s, 3H), 2.43(s, 3H). 134

22, 1 MS (ESI+): m/z 321 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.80-7.84 (m,2H), 7.39-7.44 (t, J = 8.69 Hz, 2H), 6.82-6.85 (d, J = 9.81 Hz, 2H),5.75 (s, 1H), 2.49 (s, 3H), 2.42 (s, 3H). 135

8, 1 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.28 (s, 1H),7.40-7.38 (m, 1H), 7.34-7.25 (m, 1H), 7.18- 7.15 (d, J = 7.92 Hz, 1H),7.10-7.08 (d, J = 7.71 Hz, 1H), 6.55-6.54 (m, 1H), 2.23 (s, 3H), 2.03(s, 3H). 136

18, 1 MS (ESI+): m/z 219 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.07 (s, 1H),7.07 (s, 1H), 6.44- 6.41 (d, J = 8.13 Hz, 1H), 5.80- 5.79 (d, J = 2.10Hz, 1H), 5.38-5.34 (dd, J = 8.42 Hz, J = 3.30 Hz, 1H), 2.81- 2.65 (m,4H), 1.85- 1.76 (m, 4H). 137

18, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.04 (s, 1H),6.41-6.38 (d, J = 8.07 Hz, 1H), 5.74-5.72 (m, 1H), 5.35-5.31 (m, 1H),2.70-2.65 (m, 2H), 2.54- 2.49 (m, 2H), 2.31 (s, 3H), 1.78-1.76 (m, 4H).138

19, 1 MS (ESI+): m/z 213 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 9.09 (s, 1H),8.71-8.69 (d, J = 5.61 Hz, 1H), 8.57-8.54 (d, J = 9.00 Hz, 1H), 8.26 (s,1H), 7.96-7.94 (dd, J = 5.64 Hz, J = 1.23 Hz, 1H), 7.75-7.72 (d, J =8.73 Hz, 1H), 7.37- 7.32 (m, 1H), 7.22-7.17 (m, 1H). 139

20, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 9.34 (s, 1H),8.91-8.89 (d, J = 6.06 Hz, 2H), 8.79-8.77 (d, J = 6.39 Hz, 1H),8.28-8.26 (d, J = 6.84 Hz, 1H), 7.91- 7.88 (d, J = 9.09 Hz, 1H),7.38-7.34 (d, J = 9.08 Hz, J = 1.70 Hz, 1H). 140

20, 1 MS (ESI+): m/z 248 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 9.31 (s, 1H),8.82-8.74 (m, 3H), 8.30-8.27 (d, J = 6.69 Hz, 1H), 7.94-7.93 (d, J =1.65 Hz, 1H), 7.53-7.50 (dd, J = 9.39 Hz, J = 1.92 Hz, 1H). 141

1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.10 (s, 1H),6.42-6.39 (dd, J = 8.04 Hz, J = 1.35 Hz, 1H), 5.83-5.82 (m, 1H), 5.34-5.30 (dd, J = 8.06 Hz, J = 3.53 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H),2.17 (s, 3H). 142

1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.10 (s, 1H),6.42-6.39 (dd, J = 8.04 Hz, J = 1.31 Hz, 1H), 5.83-5.82 (d, J = 2.64 Hz,1H), 5.35-5.31 (dd, J = 8.04 Hz, J = 3.67 Hz, 1H), 2.54-2.46 (q, 2H),2.19 (s, 3H), 2.17 (s, 3H), 1.31- 1.25 (t, J = 7.67 Hz, 3H). 143

1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.09 (s, 1H),6.41-6.39 (d, J = 7.77 Hz, 1H), 5.83-5.82 (s, 1H), 5.35-5.34 (d, J =4.80 Hz, 1H), 2.86-2.77 (m, 1H), 2.19 (s, 3H), 2.17 (s, 3H), 1.32-1.30(m, 6H). 144

1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.78-7.76 (m, 3H),7.67-7.62 (m, 2H), 7.10 (s, 1H), 6.62- 6.59 (d, J = 7.71 Hz, 1H),5.99-5.98 (d, J = 3.27 Hz, 1H), 5.53-5.49 (dd, J = 7.50 Hz, J = 3.63 Hz,1H), 2.25 (s, 3H), 2.149 (s, 3H). 145

1 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.05 (s, 1H), 7.11(s, 1H), 6.27 (s, 1H), 5.75 (s, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 1.62(s, 3H). 146

24, 1 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.18 (s, 1H),7.39-7.30 (m, 5H), 7.04 (s, 1H), 6.39 (s, 1H), 6.35 (s, 1H), 2.25 (s,3H), 2.14 (s, 3H). 147

1 MS (ESI+): m/z 228 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.24 (s, 1H), 7.17(s, 1H), 6.80 (s, 1H), 6.00 (s, 1H), 2.22 (s, 3H), 2.19 (s, 3H). 148

1 MS (ESI+): m/z 223 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.99 (s, 1H), 7.06(s, 1H), 6.05 (s, 1H), 5.84 (s, 1H), 3.64 (s, 3H), 2.18 (s, 3H), 2.16(s, 3H). 149

1 MS (ESI+): m/z 222 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.01 (s, 1H), 6.10(s, 1H), 5.42 (s, 1H), 2.19 (s, 3H), 2.16 (s, 3H), 1.60 (s, 3H). 150

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.06 (s, 1H), 6.58(s, 1H), 5.64 (s, 1H), 2.20 (s, 3H), 2.17 (s, 3H). 151

1 MS (ESI+): m/z 226 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.07 (s, 1H),6.50-6.46 (d, J = 6.06 Hz, 1H), 5.85-5.83. (d, J = 3.42 Hz, 1H), 2.19(s, 3H), 2.17 (s, 3H). 152

1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.83-8.81 (d, J =6.39 Hz, 1H), 8.38- 8.35 (m, 2H), 7.95-7.93 (d, J = 6.42 Hz, 1H), 7.75-7.63 (m, 4H), 2.71 (s, 3H), 2.31 (s, 3H). 153

25, 1 MS (ESI+): m/z 258 (MH⁺); ¹H NMR (300 MHz, CDCl₃): δ 6.91 (s, 1H),6.45 (s, 1H), 5.56. (s, 1H), 3.77 (s, 3H), 2.11 (s, 3H), 2.07 (s, 3H).154

11, 1 MS (ESI+): m/z 226 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.57 (s, 1H),6.47-6.45 (d, J = 6.06 Hz, 1H), 5.76-5.75. (d, J = 3.36 Hz, 1H), 2.21(s, 3H), 2.43 (s, 3H). 155

22, 1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.67-7.64 (m,2H), 7.51-7.41 (m, 3H), 6.95 (s, 1H), 6.58 (s, 1H), 5.69 (s, 1H), 2.22(s, 3H), 2.17 (s, 3H). 156

24, 22, 1 MS (ESI+): m/z 297 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.37-7.28(m, 5H), 7.02 (s, 1H), 6.88 (s, 1H), 6.29 (s, 1H), 2.62- 2.55 (q, 2H),2.26 (s, 3H), 2.13 (s, 3H), 1.32-1.27 (t, J = 7.67 Hz, 3H). 157

1 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.20 (s, 1H), 6.86(s, 1H), 6.13 (s, 1H), 2.23 (s, 3H), 2.20 (s, 3H). 158

22, 1 MS (ESI+): m/z 255 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.15 (s, 1H),6.76 (s, 1H), 5.94 (s, 1H), 2.59-2.52 (q, 2H), 2.22 (s, 3H), 2.19 (s,3H), 1.32-1.27 (t, J = 7.65 Hz, 3H). 159

23, 1 MS (ESI+): m/z 241 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.13 (s, 1H), 5.93 (s, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.11 (s, 3H).160

23, 1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),7.13 (s, 1H), 5.92 (s, 1H), 2.21 (s, 3H), 2.18 (s, 3H), 2.01-1.91 (m,1H), 1.06-1.02 (m, 2H), 0.87- 0.83 (m, 2H). 161

24, 1 MS (ESI+): m/z 287 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.18 (s, 1H),7.42-7.37 (m, 2H), 7.10-7.04 (m, 3H), 6.90 (s, 1H), 6.32 (s, 1H), 2.25(s, 3H), 2.14 (s, 3H). 162

24, 1 MS (ESI+): m/z 303 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.21 (s, 1H),7.41 (s, 1H), 7.31- 7.29 (m, 3H), 7.06 (s, 1H), 6.99 (s, 1H), 6.37 (s,1H), 2.25 (s, 3H), 2.14 (s, 3H). 163

22, 1 MS (ESI+): m/z 321 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.83-7.78 (m,2H), 7.45-7.39 (m, 2H), 7.17 (s, 1H), 6.91 (s, 1H), 6.08 (s, 1H), 2.27(s, 3H), 2.21 (s, 3H). 164

22, 1 MS (ESI+): m/z 287 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.73-7.68 (m,1H), 7.58-7.51 (m, 3H), 7.13 (s, 1H), 6.58- 6.55 (m, 1H), 5.99-5.98 (m,1H), 5.54-5.51 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H). 165

22, 1 MS (ESI+): m/z 287 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.82-7.77 (m,2H), 7.44-7.38 (m, 2H), 7.12 (s, 1H), 6.59- 6.56 (m, 1H), 5.97-5.96 (m,1H), 5.53-5.49 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H). 166

21, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.22 (s, 1H),7.11 (s, 1H), 6.55- 6.52 (d, J = 8.16 Hz, 1H), 5.84 (s, 1H), 5.53-5.49(dd, J = 8.12 Hz, J = 3.53 Hz, 1H), 3.73-3.66 (q, 2H), 2.19 (s, 3H),2.17 (s, 3H), 1.32-1.27 (t, J = 6.77 Hz, 3H). 167

21, 1 MS (ESI+): m/z 251 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),7.11 (s, 1H), 6.53- 6.50 (d, J = 8.07 Hz, 1H), 5.83 (s, 1H), 5.50-5.46(dd, J = 8.12 Hz, J = 3.53 Hz, 1H), 3.86-3.78 (m, 2H), 3.70-3.59 (m,2H), 3.42 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H). 168

21, 1 MS (ESI+): m/z 237 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),7.12 (s, 1H), 6.51- 6.48 (d, J = 8.22 Hz, 1H), 5.85-5.84 (m, 1H), 5.50-5.46 (dd, J = 8.12 Hz, J = 3.53 Hz, 1H), 3.79-3.76 (m, 2H), 3.71-3.68(m, 2H), 2.19 (s, 3H), 2.18 (s, 3H). 169

22, 1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.14 (s, 1H),6.67 (s, 1H), 5.86 (s, 1H), 2.21 (s, 3H), 2.108 (s, 3H), 1.93-1.87 (m,1H), 1.36-1.23 (m, 4H). 170

24, 1 MS (ESI+): m/z 283 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.37-7.29 (m,5H), 7.02 (s, 1H), 6.89 (s, 1H), 6.29 (s, 1H), 2.03 (s, 3H), 2.26 (s,3H), 2.14 (s, 3H). 171

31, 1 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.06 (s, 1H),5.57 (s, 1H), 2.23 (s, 3H), 2.19 (s, 3H), 2.17 (s, 3H), 1.85-1.66 (m,8H). 172

32, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.09 (s, 1H),6.20 (s, 1H), 5.73 (s, 1H), 2.22 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H),1.96- 1.94 (q, 2H), 1.06-1.01 (t, J = 7.44 Hz, 3H). 173

32, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.10 (s, 1H),6.22 (s, 1H), 5.70 (s, 1H), 2.53-2.45 (q, 2H), 2.24 (s, 3H), 2.18 (s,3H), 1.61 (s, 3H), 1.29-1.24 (t, J = 7.67 Hz, 3H). 174

22, 1 MS (ESI+): m/z 241 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.15 (s, 1H),6.76 (s, 1H), 5.94 (s, 1H), 2.29 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H).175

30, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.04 (s, 1H),7.08 (s, 1H), 5.63 (s, 1H), 2.24-2.23 (m, 2H), 2.20 (s, 3H), 2.16 (s,3H), 1.86-1.67 (m, 6H). 176

22, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.08 (s, 1H),6.35-6.32 (dd, J = 7.97 Hz, J = 1.25 Hz, 1H), 5.76-5.75 (d, J = 3.93 Hz,1H), 5.35-5.31 (m, 1H), 2.17 (s, 6H), 1.88-1.83 (m, 1H), 1.30-1.25 (m,4H). 177

22, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.10 (s, 1H),6.22 (s, 1H), 5.69 (s, 1H), 2.22 (s, 3H), 2.21 (s, 3H), 2.18 (s, 3H),1.61 (s, sH). 178

24, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.05 (s, 1H),7.10 (s, 1H), 6.26 (s, 1H), 5.79 (s, 1H), 2.22 (s, 3H), 2.17 (s, 3H),1.97- 1.95 (q, 2H), 1.06-1.02 (t, J = 7.43 Hz, 3H). 179

28, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.29 (s, 1H),7.59-7.57 (d, J = 5.37 Hz, 1H), 7.10 (s, 1H), 6.95- 6.94 (d, J = 5.34Hz, 1H), 6.79 (s, 1H), 2.34 (s, 3H), 2.18 (s, 3H). 180

32, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.09 (s, 1H),6.20 (s, 1H), 5.73 (s, 1H), 2.53-2.46 (q, 2H), 2.21 (s, 3H), 2.17 (s,3H), 1.98-1.91 (q, 2H), 1.29- 1.24 (t, J = 7.68 Hz, 3H), 1.06-1.01 (t, J= 7.42 Hz, 3H) 181

22, 1 MS (ESI+): m/z 321 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.71-7.67 (m,1H), 7.60-7.53 (m, 3H), 7.18 (s, 1H), 6.92 (s, 1H), 6.11 (s, 1H), 2.28(s, 3H), 2.21 (s, 3H). 182

26, 1 MS (ESI+): m/z 240 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.06 (s, 1H),6.47-6.45 (d, J = 5.88 Hz, 1H), 5.85-5.83. (d, J = 3.72 Hz, 1H), 2.92(s, 3H), 2.19 (s, 3H), 2.17 (s, 3H). 183

26, 1 MS (ESI+): m/z 254 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.05 (s, 1H),6.46-6.44 (d, J = 5.49 Hz, 1H), 5.85-5.83. (d, J = 4.62 Hz, 1H), 3.12(s, 6H), 2.20 (s, 3H), 2.17 (s, 3H). 184

26, 1 MS (ESI+): m/z 256 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.05 (s, 1H),6.56 (s, 1H), 5.64 (s, 1H), 2.89 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H).185

26, 1 MS (ESI+): m/z 270 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.03 (s, 1H),6.57 (s, 1H), 5.65. (s, 1H), 3.13 (s, 6H), 2.23 (s, 3H), 2.17 (s, 3H).186

21, 9, 3 MS (ESI+): m/z 269 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.20 (s,1H), 7.64-7.61 (m, 2H), 7.43-7.33 (m, 3H), 7.24 (s, 1H), 6.51-6.49 (d, J= 8.10 Hz, 1H), 5.84-5.82 (dd, J = 3.90 Hz, J = 1.20 Hz, 1H), 5.46-5.42(dd, J = 8.10 Hz, J = 3.90 Hz, 1H), 3.20 (s, 3H), 2.36 (s, 3H). 187

28, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.23 (s, 1H),7.56-7.55 (d, J = 1.50 Hz, 1H), 6.56-6.55 (d, J = 2.10 Hz, 1H), 6.57 (s,1H), 6.37 (s, 1H), 2.44 (s, 3H), 2.37 (s, 3H). 188

24, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.04 (s, 1H),7.10 (s, 1H), 6.21 (s, 1H), 5.80 (s, 1H), 2.24 (s, 3H), 2.18 (s, 3H),1.25- 1.15 (m, 1H), 0.71-0.66 (m, 3H), 0.58-0.43 (m, 1H). 189

8, 13, 1 MS (ESI+): m/z 211 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.07 (s,1H), 6.47-6.44 (d, J = 8.10 Hz, 1H), 5.90-5.87 (m, 1H), 5.39-5.35 (dd, J= 7.50 Hz, J = 3.00 Hz, 1H), 2.19 (s, 3H), 2.03 (m, 3H). 190

1 MS (ESI+): m/z 225 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.16 (s, 1H),6.67-6.65 (d, J = 6.30 Hz, 1H), 6.13 (s, 1H), 2.29 (s, 3H), 2.20 (s,3H), 2.19 (s, 3H). 191

21, 3 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s, 1H),7.16 (s, 1H), 6.47- 6.44 (d, J = 7.80 Hz, 1H), 5.83-5.82 (d, J = 3.30Hz, 1H), 5.38-5.35 (m, 1H), 3.13 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H).192

21, 3 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.20 (s, 1H),7.16 (s, 1H), 6.45- 6.43 (d, J = 7.80 Hz, 1H), 5.93-5.91 (d, J = 3.90Hz, 1H), 5.40-5.36 (dd, J = 8.10 Hz, J = 4.20 Hz, 1H), 3.55-3.47 (m,2H), 2.14 (s, 3H), 2.06 (s, 3H), 1.40-1.27 (m, 3H). 193

21, 11, 3 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.17 (s,1H), 6.60 (s, 1H), 6.45- 6.43 (d, J = 7.80 Hz, 1H), 5.74-5.73 (d, J =2.70 Hz, 1H), 5.37-5.33 (dd, J = 7.80 Hz, J = 3.60 Hz, 1H), 3.31 (s,3H), 2.49 (s, 3H), 2.30 (s, 3H). 194

28, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.25 (s, 1H),7.59-7.58 (dd, J = 2.10 Hz, J = 0.60 Hz, 1H), 7.11 (s, 1H), 6.73 (s,1H), 6.58-6.57 (d, J = 2.10 Hz, 1H), 2.23 (s, 3H), 2.18 (s, 3H). 195

30, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.09 (s, 1H),7.09 (s, 1H), 5.96 (s, 1H), 2.62-2.57 (m, 2H), 2.35-2.30 (m, 2H), 2.18(s, 3H), 2.17 (s, 3H), 2.21- 1.91 (m, 2H). 196

32, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.08 (s, 1H),6.24 (s, 1H), 5.77 (s, 1H), 2.23 (s, 3H), 2.22 (s, 3H), 2.18 (s, 3H),2.17- 2.13 (m, 1H), 1.07-1.03 (m, 6H). 197

29, 3 MS (ESI+): m/z 318 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.15 (s, 1H),6.88 (s, 1H), 6.41- 6.38 (dd, J = 8.10 Hz, J = 1.20 Hz, 1H), 5.50-5.48(dd, J = 3.30 Hz, J = 1.80 Hz, 1H), 5.35-5.31 (dd, J = 8.40 Hz, J = 3.00Hz, 1H), 3.86-3.82 (m, 2H), 3.78- 3.75 (m, 2H), 3.33-3.32 (m, 4H), 2.46(s, 3H), 2.42 (s, 3H). 198

21, 11, 3 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.15 (s,1H), 6.69 (s, 1H), 6.44- 6.43 (d, J = 8.10 Hz, 1H), 5.76-5.74 (dd, J =3.60 Hz, J = 1.20 Hz, 1H), 5.38- 5.34 (dd, J = 7.50 Hz, J = 3.30 Hz,1H), 3.04 (s, 3H), 2.67-2.60 (q, 2H), 2.50 (s, 3H), 1.25-1.21 (t, J =7.50 Hz, 3H). 199

21, 3 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.13 (s, 1H),6.75 (s, 1H), 6.44- 6.41 (d, J = 8.10 Hz, 1H), 5.50-5.49 (m, 1H), 5.40-5.36 (dd, J = 8.10Hz, J = 3.60 Hz, 1H), 3.68-3.60 (q, 2H), 2.43 (s, 3H),2.40 (s, 3H), 1.40-1.27 (m, 3H). 200

31, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.08 (s, 1H),5.90 (s, 1H), 2.64- 2.53 (m, 2H), 2.34-2.30 (m, 2H), 2.27 (s, 3H), 2.18(s, 3H), 2.17 (s, 3H), 2.10- 1.96 (m, 2H). 201

21, 3 MS (ESI+): m/z 207 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.07 (s, 1H),6.79 (s, 1H), 6.34- 6.30 (m, 1H), 5.49-5.47 (m, 1H), 5.37-5.33 (dd, J =8.16 Hz, J = 3.36 Hz, 1H), 3.34 (s, 3H), 2.42 (s, 3H), 2.40 (s, 3H). 202

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.15 (s, 1H),7.88-7.85 (dd, J = 7.80 Hz, J = 2.40 Hz, 2H), 7.44-7.34 (m, 2H), 6.30(s, 1H), 6.05 (s, 1H), 2.65 (s, 3H), 1.49 (s, 3H). 203

1 MS (ESI+): m/z 263 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.32 (s, 1H),7.89-7.87 (d, J = 7.50 Hz, 1H), 7.82-7.80 (d, J = 7.50 Hz, 1H),7.46-7.36 (m, 2H), 6.86-6.85 (d, J = 0.6 Hz, 1H), 6.26-6.25 (d, J = 1.2Hz, 1H), 2.66 (s, 3H). 204

1 MS (ESI+): m/z 243 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.89-7.84 (m, 2H),7.44-7.33 (m, 2H), 6.45-6.42 (dd, J = 8.10 Hz, J = 1.80 Hz, 1H),6.09-6.07 (m, 1H), 5.27- 5.23 (dd, J = 8.10 Hz, J = 3.00 Hz, 1H), 2.63(s, 3H), 2.28 (s, 3H). 205

1 MS (ESI+): m/z 278 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.85-7.83 (m, 1H),7.76-7.73 (m, 1H), 7.41-7.32 (m, 2H), 6.66 (s, 1H), 5.91 (s, 1H), 2.64(s, 3H). 206

33, 4 MS (ESI+): m/z 297 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.43 (s, 1H),7.87-7.84 (m, 1H), 7.52-7.50 (m, 1H), 7.34- 7.29 (m, 2H), 6.99-6.84 (m,3H), 6.70 (s, 1H), 2.67 (s, 3H). 207

24, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.03 (s, 1H),7.10 (s, 1H), 6.29 (s, 1H), 5.82 (s, 1H), 2.23 (s, 3H), 2.18 (s, 3H),2.17- 2.14 (m, 1H), 1.09-1.04 (m, 6H). 208

33, 13, 4 MS (ESI+): m/z 301 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.50 (s,1H), 7.88-7.85 (m, 1H), 7.63-7.60 (m, 1H), 7.45- 7.41 (m, 2H), 7.09-6.98(m, 3H), 6.7 (s, 1H) 209

33, 13, 4 MS (ESI+): m/z 301 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.46 (s,1H), 7.88-7.85 (m, 1H), 7.65-7.62 (m, 1H), 7.46- 7.39 (m, 2H), 7.30-7.22(m, 2H), 6.87-6.84 (m, 1H), 6.75 (s, 1H) 210

26, 13, 4 MS (ESI+): m/z 296 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.87-7.85(d, J = 7.5 Hz, 1H), 7.76- 7.74 (d, J = 7.2 Hz, 1H), 7.48-7.43 (m, 2H),6.69 (s, 1H), 5.88 (s, 1H), 2.89 (s, 3H) 211

15, 13, 4 MS (ESI+): m/z 251 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.25 (s,1H), 7.91-7.87 (m, 1H), 7.64-7.60 (dd, J = 9.81 Hz, J = 2.46 Hz, 1H),7.28- 7.22 (td, J = 8.97 Hz, J = 2.54 Hz , 1H), 6.52-6.50 (d, J = 8.29Hz, 1H), 6.03- 6.01 (m, 1H), 5.41-5.36 (m, 1H) 212

13, 1 MS (ESI+): m/z 282 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.87-7.84 (d,J = 7.20 Hz, 1H), 7.77- 7.75 (d, J = 7.35 Hz, 1H), 7.50-7.40 (m, 2H),6.70 (s, 1H), 5.87 (s, 1H) 213

1 MS (ESI+): m/z 225 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.38 (s, 1H),7.90-7.82 (dd, J = 10.5 Hz, J = 7.5 Hz, 2H), 7.55-7.46 (m, 2H), 6.90 (s,1H), 6.20 (s, 1H), 214

5, 1 MS (ESI+): m/z 309 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.11 (s, 1H),7.99-7.96 (m, 1H), 7.51-7.30 (m, 8H), 6.44- 6.40 (m, 1H), 5.81-5.80 (m,1H), 5.48-5.44 (m, 1H) 215

5, 1 MS (ESI+): m/z 325 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.12 (s, 1H),8.00-7.97 (d, J = 7.77 Hz, 1H), 7.68-7.65 (m, 1H), 7.58-7.39 (m, 5H),7.27-7.25 (m, 1H), 6.41- 6.38 (d, J = 8.19 Hz, 1H), 5.63-5.62 (m, 1H),5.44- 5.41 (dd, J = 8.13 Hz, J = 3.24 Hz, 2H) 216

5, 1 MS (ESI+): m/z 291 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.08-8.05 (m,2H), 7.99-7.97 (d, J = 7.17 Hz, 1H), 7.54-7.47 (m, 7H), 6.40-6.37 (d, J= 8.16 Hz, 1H), 6.00-5.99 (t, J = 2.37 Hz, 1H), 5.39- 5.36 (dd, J = 8.24Hz, J = 2.04 Hz, 1H) 217

30, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.08 (s, 1H),6.67 (s, 1H), 5.64 (s, 1H), 2.61-2.56 (m, 2H), 2.42 (s, 6H), 2.39-2.27(m, 1H), 2.11-1.98 (m, 3H) 218

31, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.65 (s, 1H),5.74 (s, 1H), 2.59- 2.53 (m, 2H), 2.42 (s, 3H), 2.39 (s, 3H), 2.29 (s,3H), 2.09-2.01 (m, 4H) 219

1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.01 (s, 1H), 6.69(s, 1H), 6.23 (s, 1H), 5.50 (s, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.03-2.02 (m, 1H), 1.06-0.99 (dd, J = 10.2 Hz, J = 6.9 Hz, 6H) 220

28, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.23 (s, 1H),7.56-7.55 (m, 1H), 6.56-6.55 (m, 1H), 6.37 (s, 1H), 6.38 (s, 1H), 2.44(s, 3H), 2.39 (s, 3H) 221

32, 1 MS (ESI+): m/z 235 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.67 (s, 1H),6.17 (s, 1H), 5.37 (s, 1H), 2.53-2.42 (q, 2H), 2.40 (s, 3H), 2.39 (s,3H), 1.54 (s, 3H), 1.30-1.25 (t, J = 8.4 Hz, 3H) 222

22, 1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.70 (s, 1H),6.63 (s, 1H), 5.53 (s, 1H), 2.43 (s, 3H), 2.42 (s, 3H), 1.94-1.87 (m,1H), 1.36-1.27 (m, 3H), 1.19- 1.11 (m, 1H) 223

13, 1 MS (ESI+): m/z 267 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.78 (s, 1H),6.61-6.59 (d, J = 6.3 Hz, 1H), 5.78 (s, 1H), 2.42 (s, 3H), 2.27 (s, 3H)224

28, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.26 (s, 1H),7.23-7.21 (d, J = 5.4 Hz, 1H), 6.60-6.58 (d, J = 5.4 Hz, 1H), 6.54 (s,1H), 6.25 (s, 1H), 2.45 (s, 3H), 2.36 (s, 3H) 225

1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.01 (s, 1H), 6.71(s, 1H), 6.14 (s, 1H), 5.48 (s, 1H), 2.45 (s, 3H), 2.40 (s, 3H),1.07-1.06 (m, 1H), 0.68-0.64 (m, 2H), 0.63-0.60 (m, 2H) 226

28, 1 MS (ESI+): m/z 249 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.26 (s, 1H),7.55-7.53 (d,J = 5.1 Hz, 1H), 6.94-6.92 (d, J = 5.4 Hz, 1H), 6.60 (s,1H), 6.44 (s, 1H), 2.45 (s, 3H), 2.37 (s, 3H) 227

22, 1 MS (ESI+): m/z 233 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.70 (s, 1H),6.33-6.30 (d, J = 8.83 Hz, 1H), 5.43 (s, 1H), 5.22- 5.18 (dd, J = 8.00Hz, J = 3.59 Hz, 1H), 2.40 (s, 6H), 1.96-1.87 (m, 1H), 1.30- 1.14 (m,4H) 228

32, 1 MS (ESI+): m/z 221 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.01 (s, 1H),6.69 (s, 1H), 6.18 (s, 1H), 5.45 (s, 1H), 2.42 (s, 3H), 2.39 (s, 3H),1.89- 1.84 (q, 2H), 1.03-1.01 (t, J = 7.2 Hz, 3H) 229

31, 1 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.65 (s, 1H),5.27 (s, 1H), 2.40 (s, 6H), 2.22 (s, 3H), 2.19- 2.18 (m, 2H), 1.79-1.62(m, 6H) 230

30, 1 MS (ESI+): m/z 247 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.00 (s, 1H),6.67 (s, 1H), 5.30 (s, 1H), 2.40 (s, 6H), 2.20- 2.19 (m, 2H), 1.80-1.62(m, 6H) 231

33, 4 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.32 (s, 1H),7.02-6.90 (m, 3H), 6.53 (s, 1H), 6.17 (s, 1H), 2.48 (s, 3H), 2.35 (s,3H)  2

33, 4 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.27 (s, 1H),7.20-7.14 (m, 2H), 6.72-6.68 (dd, J = 8.7 Hz, J = 2.7 Hz, 1H), 6.53 (s,1H), 6.19 (s, 1H), 2.49 (s, 3H), 2.36 (s, 3H) 233

33, 4 MS (ESI+): m/z 275 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.23-7.19 (m,2H), 6.76-6.73 (m, 1H), 6.54 (s, 1H), 6.18 (s, 1H), 2.49 (s, 3H), 2.43(s, 3H), 2.35 (s, 3H) 234

33, 4 MS (ESI+): m/z 261 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.29 (s, 1H),7.27-7.21 (m, 2H), 6.79-6.76 (m, 1H), 6.55 (s, 1H), 6.22 (s, 1H), 2.49(s, 3H), 2.35 (s, 3H) 235

33, 4 MS (ESI+): m/z 275 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 7.15-7.12 (m,2H), 6.68-6.65 (d, J = 8.4 Hz, 1H), 6.52 (s, 1H), 6.15 (s, 1H), 2.49 (s,3H), 2.38 (s, 3H), 2.36 (s, 3H) 236

33, 4 MS (ESI+): m/z 275 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 6.99-6.94 (m,2H), 6.89-6.85 (dd, J = 9.3 Hz, J = 2.4 Hz, 1H), 6.52 (s, 1H), 6.12 (s,1H), 2.48 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H) 237

12, 1 MS (ESI+): m/z 272 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.14 (s, 1H),6.84 (s, 1H), 6.49- 6.47 (d, J = 8.4 Hz, 1H), 5.86-5.85 (dd, J = 3.6 Hz,J = 1.2 Hz, 1H), 5.40-5.37 (m, 1H), 2.91-2.83 (q, 2H), 1.33-1.28 (t, J =7.5 Hz, 3H) 238

20, 1 MS (ESI+): m/z 298 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.23 (s, 1H),8.10 (s, 1H), 8.04 (s, 1H), 6.51-6.48 (m, 1H), 6.11-6.10 (t, J = 2.4 Hz,1H), 5.32-5.28 (m, 1H), 2.65 (s, 3H) 239

33, 13, 4 MS (ESI+): m/z 301 (MH⁺); ¹H NMR (300 MHz, MeOD): δ 8.50 (s,1H), 7.88-7.85 (m, 1H), 7.63-7.60 (m, 1H), 7.45- 7.41 (m, 2H), 7.09-6.98(m, 3H), 6.7 (s, 1H)

B. Animal Models

Anti-psychotic like activity of the compounds was evaluated in miceusing the PCP hyperactivity (in rats) and Pre-Pulse Inhibition (PPI; inmice) models of schizophrenia.

1. Methods

Animals: PCP Hyperactivity: Male Sprague Dawley rats from Harlan(Indianapolis, Ind.) were used in these studies. Upon receipt, rats wereassigned unique identification numbers and were group housed with 3 ratsper cage in polycarbonate cages with micro-isolator filter tops. Allrats were examined, handled, and weighed prior to initiation of thestudy to assure adequate health and suitability. The rats weremaintained at 12/12 light/dark cycle with lights on at 7:00 am EST. Theroom temperature was maintained between 20 and 23° C. with a relativehumidity maintained around 50%. Chow and water were provided ad libitumfor the duration of the study. For each test, animals were randomlyassigned across treatment groups.

Animals—PPI: Male C57B1/6J mice from Jackson Laboratories (Bar Harbor,Me.) were used in these studies. Upon receipt, mice were assigned uniqueidentification numbers (tail marked) and were group housed with 4 miceper cage in OptiMICE ventilated cages. All animals remained housed ingroups of four during the remainder of the study. All mice wereacclimated to the colony room for at least one week prior to testing.During the period of acclimation, mice were examined on a regular basis,handled, and weighed to assure adequate health and suitability. Animalswere maintained on a 12/12 light/dark cycle. The room temperature wasmaintained between 20 and 23° C. with a relative humidity maintainedbetween 30% and 70%. Chow and water were provided ad libitum for theduration of the study. In each test, animals were randomly assignedacross treatment groups.

2. PCP Hyperactivity

The test chambers were Plexiglas rectangular chambers (24×45 cm) thatfit inside two steel frames (9.5×18 inches) and were fitted withtwo-dimensional 4×8 beam grids to monitor horizontal and verticallocomotor activity (Hamilton Kinder, San Diego, Calif.). The analysiswas configured to divide the open field of the chamber into a center anda periphery zone. Distance traveled was measured from horizontal beambreaks as the rat traveled whereas rearing activity was measured fromvertical beam breaks.

Rats were administered with vehicle, test compound, or risperidone(0.5-1 mg/kg; i.p) and placed in the test chambers for 30 minmeasurement of baseline activity. Rats were then injected with eitherwater or PCP (2.5 mg/kg; s.c) and placed back in the test chambers for a60-minute session. At the end of each test session the chambers werethoroughly cleaned.

3. Prepulse Inhibition of Startle

The acoustic startle is an unconditioned reflex response to an externalauditory stimulus. Prepulse inhibition of startle (PPI) refers to thereduction in the startle response caused by the presentation of alow-intensity auditory stimulus prior to the startle stimulus. The PPIparadigm is used for the study of schizophrenia and antipsychotic actiondue to the similarities between the results from human and rodentstudies. PPI has been used as a tool for the assessment of deficienciesin sensory-motor gating observed in schizophrenia and to screen forpotential antipsychotic drugs. Various psychotomimetic drugs such as PCPcan disrupt PPI. In mice, antipsychotic drugs such as clozapine canreverse the disruption of PPI induced by PCP.

Mice were placed in the PPI chambers (Med Associates) for a 5 minsession of white noise (70 dB) habituation. After the habituation periodthe test session was initiated. The session started with a habituationblock of 6 presentations of the startle stimulus alone, followed by 10PPI blocks, each of which consisted of 6 different types of trials.Trial types were: ‘null’ (no stimuli), ‘startle’ (120 dB), ‘startle plusprepulse’ (4, 8 and 12 dB over background noise, i.e., 74, 78 or 82 dB)and ‘prepulse’ (82 dB). Trial types were presented in a random orderwithin each block. Each trial started with a 50 ms stimulus-free periodduring which baseline movements were recorded. This was followed by asubsequent 20 ms period during which the prepulse stimulus was presentedand responses to the prepulse measured. After a further 100 ms period,the startle stimulus was presented for 40 ms and responses recorded for100 ms from startle onset. Responses were sampled every ms. Theinter-trial interval was variable with an average of 15 s (range from 10to 20 s). In ‘startle’ trials the basic auditory startle response wasmeasured. The basic startle response was calculated as the mean startleresponse of all ‘startle’ trials (i.e., excluding the first habituationblock). In ‘startle plus prepulse’ trials the degree of inhibition ofthe normal startle was calculated and expressed as a percentage of thebasic startle response.

Mice were treated with vehicle, haloperidol (1 mg/kg;i.p) or testcompound 30 min prior to PPI test. The PPI enclosures were cleanedfollowing each test.

4. Results

TABLE 1 Effects of Compounds on Pre-pulse Inhibition (PPI) in MiceCompound/Doses Effect 21 3 mg/kg − 10 mg/kg − 30 mg/kg −  3 3 mg/kg + 10mg/kg + 30 mg/kg +++ 15 3 mg/kg − 10 mg/kg + 30 mg/kg ++ 239  3 mg/kg −10 mg/kg − 30 mg/kg +++ 20 3 mg/kg − 10 mg/kg − 30 mg/kg − *P < 0.05 vs.vehicle −: No change in PPI +: Significant increase in PPI at onepre-pulse intensity (P value < 0.05) ++: Significant increase in PPI attwo pre-pulse intensities (P value < 0.05) +++: Significant increase inPPI at three pre-pulse intensities (P value < 0.05)

TABLE 2 Effects of Compounds on PCP-Induced Hyperactivity Responses inRats Compound/Doses Total Distance Traveled (cm) 21 10 mg/kg Compound +PCP − 30 mg/kg Compound + PCP − 100 mg/kg Compound + PCP  −  3  3 mg/kgCompound + PCP − 10 mg/kg Compound + PCP + 30 mg/kg Compound + PCP + 15 3 mg/kg Compound + PCP − 10 mg/kg Compound + PCP − 30 mg/kg Compound +PCP − 239   3 mg/kg Compound + PCP + (increase) 10 mg/kg Compound +PCP + (increase) 30 mg/kg Compound + PCP + (increase) 20  3 mg/kgCompound + PCP + 10 mg/kg Compound + PCP − 30 mg/kg Compound + PCP + *P< 0.05 vs. vehicle + PCP −: No inhibition of PCP hyperactivity +:Significant inhibition of PCP hyperactivity (P value < 0.05)

The embodiments described above are intended to be merely exemplary, andthose skilled in the art will recognize, or will be able to ascertainusing no more than routine experimentation, numerous equivalents ofspecific compounds, materials, and procedures. All such equivalents areconsidered to be within the scope of the disclosure and are encompassedby the appended claims.

All of the patents, patent applications and publications referred toherein are incorporated by reference herein in their entireties.Citation or identification of any reference in this application is notan admission that such reference is available as prior art to thisapplication. The full scope of the disclosure is better understood withreference to the appended claims.

What is claimed:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein X is selectedfrom S and O; one of R^(1a) and R^(1b) is

wherein R⁵ is selected from hydrogen, alkyl, and C₃₋₂₀ cycloalkyl; R⁶ isselected from hydrogen, cyano, amino, alkylamino, alkyl, alkoxyl,alkenyl, alkynyl, C₃₋₂₀ cycloalkyl, C₃₋₂₀ cycloalkyl-C₁₋₂₀ alkyl, C₆₋₂₀aryl, C₆₋₂₀ aryl-C₁₋₂₀ alkyl, C₃₋₂₀ heterocyclyl with 1-2 heteroatomsselected from O, N, S, and combinations thereof, and C₅₋₂₀ heteroarylwith 1-2 heteroatoms selected from O, N, S, and combinations thereof,R⁷, and R⁸ are each independently selected from hydrogen, halo, cyano,amino, alkylamino, alkyl, alkoxyl, alkenyl, alkynyl, C₃₋₂₀ cycloalkyl,C₃₋₂₀ cycloalkyl-C₁₋₂₀ alkyl, C₆₋₂₀ aryl, C₆₋₂₀ aryl-C₁₋₂₀ alkyl, C₃₋₂₀heterocyclyl with 1-2 heteroatoms selected from O, N, S, andcombinations thereof, and C₅₋₂₀ heteroaryl with 1-2 heteroatoms selectedfrom O, N, S, and combinations thereof; and the other of R^(1a) andR^(1b) is selected from hydrogen, halo, cyano, alkyl, alkoxyl, alkenyl,alkynyl, C₃₋₂₀ cycloalkyl, C₃₋₂₀ cycloalkyl-C₁₋₂₀ alkyl, C₆₋₂₀ aryl,C₆₋₂₀ aryl-C₁₋₂₀ alkyl, C₃₋₂₀ heterocyclyl with 1-2 heteroatoms selectedfrom O, N, S, and combinations thereof, and C₅₋₂₀ heteroaryl with 1-2heteroatoms selected from O, N, S, and combinations thereof; and R² andR³ and the atoms to which they are attached form a benzene ring, whereineach amino, alkylamino, alkyl, alkoxyl, alkenyl, alkynyl, C₃₋₂₀cycloalkyl, C₃₋₂₀ cycloalkyl-C₁₋₂₀ alkyl, C₆₋₂₀ aryl, benzene ring,C₆₋₂₀ aryl-C₁₋₂₀ alkyl, C₃₋₂₀ heterocyclyl, and C₅₋₂₀ heteroaryl thereofis optionally substituted.
 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein one of R^(1a) andR^(1b) is selected from hydrogen, halo, cyano, alkyl, alkoxyl, alkenyl,alkynyl, C₃₋₂₀ cycloalkyl, C₃₋₂₀ cycloalkyl-C₁₋₂₀ alkyl, C₆₋₂₀ aryl, andC₆₋₂₀ aryl C₁₋₂₀ alkyl.
 3. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R^(1a) is representedby the following structure:


4. The compound of claim 3, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ are each independently selected fromhydrogen, halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl,alkynyl, C₃₋₂₀ cycloalkyl, and C₆₋₂₀ aryl.
 5. The compound of claim 4,or a pharmaceutically acceptable salt thereof, wherein R^(1a) isselected from:


6. The compound of claim 5, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein R^(1b) isrepresented by the following structure:


8. The compound of claim 7, or a pharmaceutically acceptable saltthereof, wherein R⁷ and R⁸ are each independently selected fromhydrogen, halo, cyano, amino, alkylamino, alkyl, alkoxyl, alkenyl,alkynyl, C₃₋₂₀ cycloalkyl, and C₆₋₂₀ aryl.
 9. The compound of claim 8,or a pharmaceutically acceptable salt thereof, wherein R^(1b) isselected from:


10. The compound of claim 8, or a pharmaceutically acceptable saltthereof, wherein R⁵ is hydrogen or alkyl; R⁶ is selected from hydrogen,amino, alkylamino, alkyl, alkoxyl, C₃₋₂₀ cycloalkyl, and C₆₋₂₀ aryl; andR⁷ and R⁸ are each independently selected from hydrogen, halo, amino,alkylamino, alkyl, alkoxyl, C₃₋₂₀ cycloalkyl, and C₆₋₂₀ aryl.
 11. Thecompound of claim 9, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 12. The compound of claim1, or a pharmaceutically acceptable salt thereof, wherein X is S. 13.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein X is O.
 14. A pharmaceutical composition comprising a compoundof claim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient or carrier.
 15. A method oftreating a neurological disorder, comprising administering to a subjecta therapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof, wherein the disorder ispsychosis.
 16. A method of treating a neurological disorder, comprisingadministering to a subject a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein the disorder is schizophrenia.
 17. A pharmaceutical compositioncomprising a compound of claim 11, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient or carrier.
 18. Amethod of treating a neurological disorder, comprising administering toa subject a therapeutically effective amount of a compound of claim 11,or a pharmaceutically acceptable salt thereof, wherein the disorder ispsychosis.
 19. A method of treating a neurological disorder, comprisingadministering to a subject a therapeutically effective amount of acompound of claim 11, or a pharmaceutically acceptable salt thereof,wherein the disorder is schizophrenia.
 20. A pharmaceutical compositioncomprising a compound of claim 12, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient or carrier.
 21. Amethod of treating a neurological disorder, comprising administering toa subject a therapeutically effective amount of a compound of claim 12,or a pharmaceutically acceptable salt thereof, wherein the disorder ispsychosis.
 22. A method of treating a neurological disorder, comprisingadministering to a subject a therapeutically effective amount of acompound of claim 12, or a pharmaceutically acceptable salt thereof,wherein the disorder is schizophrenia.
 23. A pharmaceutical compositioncomprising a compound of claim 9, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable excipient or carrier.
 24. Amethod of treating a neurological disorder, comprising administering toa subject a therapeutically effective amount of a compound of claim 9,or a pharmaceutically acceptable salt thereof, wherein the disorder ispsychosis.
 25. A method of treating a neurological disorder, comprisingadministering to a subject a therapeutically effective amount of acompound of claim 9, or a pharmaceutically acceptable salt thereof,wherein the disorder is schizophrenia.